OBJECTIVES

After completing this chapter, the reader should be able to

  • Justify the need for concentration monitoring of a drug based on its characteristics and the clinical situation

  • Identify and justify information needed when requesting and reporting drug concentrations

  • Describe and categorize factors that may contribute to interpatient variation(s) in a therapeutic range of drug concentrations

  • Explain the importance of documenting the time a sample is obtained relative to the last dose as well as factors that can affect interpretation of a drug concentration, depending on when it was obtained

  • Compare linear to nonlinear pharmacokinetic behavior with respect to how drug concentration measurements are used to make dosage regimen adjustments

  • Describe how altered serum binding, active metabolites, or stereoselective pharmacokinetics can impact the interpretation of drug concentration measurements

The pharmacist is a key member in the therapeutic drug monitoring process. This chapter is designed to review the indications for drug concentration monitoring and discuss how drug concentrations obtained from the clinical laboratory, specialized reference laboratory, or physician’s office should be interpreted. General considerations for interpretation are described as well as unique considerations for drugs that commonly undergo therapeutic drug monitoring. Future directions of therapeutic drug monitoring are also discussed.

This chapter is not intended to provide an in-depth review of pharmacokinetic dosing methods; nevertheless, knowledge of certain basic pharmacokinetic terms and concepts is expected. The general phrase drug concentration will be used throughout the chapter unless specific references to serum, plasma, whole blood, and saliva are more appropriate. The bibliography lists numerous texts about therapeutic drug monitoring and clinical pharmacokinetic principles with applications to clinical practice.

THERAPEUTIC DRUG MONITORING

Therapeutic drug monitoring is broadly defined as the use of drug concentrations to optimize drug therapy for individual patients.1 Prior to using drug concentrations to guide therapy, physicians adjusted drug doses based on their interpretation of clinical response. In many cases, drug doses were increased until obvious signs of toxicity were observed (eg, nystagmus for phenytoin or tinnitus for salicylates). The idea that intensity and duration of pharmacologic response depended on serum drug concentration was first reported by Marshall and then tested for the screening of antimalarials during World War II.2,3 Koch-Weser, in a hallmark paper, described how steady-state serum concentrations of commonly used drugs can vary 10-fold among patients receiving the same dosage regimen.4 He further described how serum concentrations predict the intensity of therapeutic or toxic effects more accurately than dosage.

Starting in the 1960s, there was rapid improvement in analytical methods used for drug concentration measurements; extensive research correlating serum or plasma drug concentrations with clinical efficacy and toxicity quickly followed. Today, with the emergence of immunoassays that require no specialized equipment, drug concentration measurements can be easily performed in outpatient clinic offices.

The increased availability and convenience of drug assay methods has led to a number of concerns. Is therapeutic drug monitoring being done simply because it is available, rather than because it is clinically necessary? There are numerous reports of suboptimal therapeutic drug monitoring practices that contribute to inappropriate decision-making as well as wasted resources.57 Questions have been raised about whether therapeutic drug monitoring actually improves patient outcomes.8,9 Alternatively, many clinicians claim that therapeutic drug monitoring is greatly underused and could, if appropriately used, further improve patient care and reduce healthcare costs.1012 Clearly, there is a need for more education of all healthcare professionals involved in the therapeutic drug monitoring process to make its use more appropriate and cost-effective. Such education efforts have been shown to effectively reduce the number of inappropriate drug concentration requests.13

Goal and Indications for Drug Concentration Monitoring

The primary goal of therapeutic drug monitoring is to maximize the benefit of a drug to a patient in the shortest possible time while minimizing the risk of drug toxicity. The number of hospitalizations or office visits used to adjust therapies or manage and diagnose adverse drug reactions may therefore be reduced, resulting in overall cost savings.

Drug concentration measurements should not be performed unless the result will affect some future action or decision. Monitoring should not be done simply because the opportunity presents itself; it should be used discriminatingly to answer clinically relevant questions and resolve or anticipate problems in drug therapy management.14 The clinician should always ask, “Will this drug concentration value provide more information to me than sound clinical judgment alone?”9 The following examples provide clinical situations and clinical questions that drug concentration measurements might be able to impact:

  • Therapeutic confirmation: A patient is on a regimen that appears to offer the maximum benefit with acceptable side effects. Question: What drug concentration is associated with a therapeutic effect in this patient for future reference?

  • Dosage optimization: A patient has a condition in which the clinical response is not easily measured and has been initiated on a standard regimen of a drug. There is modest improvement, and no symptoms of toxicity are evident. Question: Can I increase the dose to further enhance the effect? If so, by how much?

  • Confirmation of suspected toxicity: A patient is experiencing certain signs and symptoms that could be related to the drug. Question: Are these signs and symptoms most likely related to a dose that is too high? Can I reduce the daily dose to maintain efficacy and if so, by how much?

  • Avoidance of inefficacy or toxicity: A patient is initiated on a standard regimen of an antibiotic that is known to be poorly absorbed in a small percentage of patients. Sustained subtherapeutic concentrations of this drug can lead to drug resistance. Question: Will a higher daily dose be needed in this patient? A patient has been satisfactorily treated on a regimen of Drug A. The patient experiences a change in health or physiologic status or a second drug, suspected to interact with Drug A, is added. Question: Will a regimen adjustment be needed to avoid inefficacy or toxicity?

  • Distinguishing nonadherence from treatment failure: A patient has not responded to usual doses and nonadherence is a possibility. Question: Is this a treatment failure, or does the patient need counseling on adherence?

Characteristics of Ideal Drugs for Therapeutic Drug Monitoring

Not all drugs are good candidates for therapeutic drug monitoring. Those for which drug concentration monitoring will be most useful have the following characteristics15:

  • Readily available assays: Methods for drug concentration measurement must be thoroughly evaluated for sensitivity, specificity, accuracy, and precision and be available to the clinician at a cost to justify the information to be gained. Chromatographic methods are most likely used in laboratory settings and are considered in many cases to be the reference methods. Increased interest in methods for use in ambulatory settings, however, has led to the development of immunoassay systems purported to be fast, reliable, and cost-effective.1620

  • Lack of easily observable, safe, or desirable clinical endpoint: Clinically, there is no immediate, easily monitored, and predictable clinical parameter to guide dose titration. For example, waiting for arrhythmias or seizures to occur or resume may be an unsafe and undesirable approach to dosing antiarrhythmics and antiepileptics.

  • Dangerous toxicity or lack of effectiveness: Toxicity or lack of effectiveness of the drug presents a danger to the patient. For example, serum concentrations of the antifungal drug, flucytosine, are not routinely monitored. However, specialized monitoring may be done to ensure that concentrations are less than 100 mg/L to avoid gastrointestinal (GI) side effects, blood dyscrasias, and hepatotoxicity. As another example, specialized monitoring of the protease inhibitors (PIs) may be done to ensure adequate concentrations because rapid emergence of antiviral resistance is observed with sustained exposure to subtherapeutic concentrations.

  • Unpredictable dose–response relationship: The presence of an unpredictable dose–response relationship, such that a dose rate that produces therapeutic benefit in one patient may cause toxicity in another patient. This would be true for drugs that have significant interpatient variation in pharmacokinetic parameters, drugs with nonlinear elimination behavior, and drugs with pharmacokinetic parameters that are affected by concomitant administration of other drugs. For example, patients given the same daily dose of phenytoin can demonstrate a wide range of serum concentrations and responses.

  • Narrow therapeutic range: The drug concentrations associated with therapeutic effect overlap considerably with the concentrations associated with toxic effects, such that the zone for therapeutic benefit without toxicity is narrow. For example, the therapeutic range of total serum concentrations of phenytoin is widely accepted to be 10 to 20 mg/L for most patients; the upper limit of the range is only twice the lower limit.

  • Good correlation between drug concentration and efficacy or toxicity: This criterion must apply if we are using drug concentrations to adjust the dosage regimen of a drug. For example, a patient showing unsatisfactory seizure control with a serum phenytoin concentration of 8 mg/L is likely to show improved control with a serum concentration of 15 mg/L.

Other than availability of an assay, it may not be necessary for a drug to fulfill the previously listed characteristics for drug concentration monitoring to help guide clinical decision-making. Newer drugs that do not yet have clearly defined therapeutic ranges may be monitored only under special circumstances (eg, to ensure adherence). Other drugs may not have a clearly defined upper or lower limit to the therapeutic range but are monitored under special circumstances to ensure efficacy or avoid toxicity. The fact remains, the drug concentration is important for answering a specific clinical question: Will the information provided by this measurement help to improve the patient’s drug therapy?

Information Needed for Planning and Evaluating Drug Concentrations

Drug concentrations should be interpreted in light of full information about the patient, including clinical status. Information surrounding the timing of the sample relative to the last dose is especially critical and is one of the biggest factors making drug concentrations unusable or cost-ineffective.5,2123 Table 5-1 provides a list of the essential information needed for a drug concentration request. Laboratory request forms or computer entry forms must be designed to encourage entry of the most important information. All relevant information should be included on both the request form and the report form to facilitate an accurate interpretation. It is particularly important to verify the time of the sample draw because phlebotomists or computer-generated labels commonly identify samples with the time of the intended draw instead of the actual draw time. Some hospital laboratories have minimized the number of inappropriate samples by refusing to run any samples that are not accompanied by critical information, such as the timing of the sample relative to the last dose; however, this practice can be cumbersome and is not widely used.5 The laboratory report form should also include the assay used; active metabolite concentration (if measured); and parameters reflecting the sensitivity, specificity, and precision of the method.

TABLE 5-1.

Information Needed to Order and/or Interpret a Laboratory Value

TYPE OF DATA

SPECIFIC DATA

WHY NECESSARY

Patient identification

  • Name, address, identification number, and physician name

All blood samples look alike and could easily be switched among patients without appropriate identification

Patient demographics and characteristics

  • Age, gender, ethnicity, height, weight, and pregnancy

The therapeutic range for a given drug may depend on the specific indication being treated (eg, digoxin for atrial arrhythmias versus heart failure); if there is no history of prior drug concentration measurements, information about concurrent disease states, physiologic status, and social habits may help with initial determination of population pharmacokinetic parameters, in order to determine if the resulting concentration is expected or not; information about renal function and albumin is important if a total drug concentration is being measured for a drug normally highly bound to serum proteins; it is also important to know if any endogenous substances due to diseases will interfere with the assay; electrolyte abnormalities may affect the interpretation of a given concentration (eg, digoxin)

History and physical examination

  • Condition being treated

  • Organ involvement (renal, hepatic, cardiac, GI, and endocrine)

  • Fluid balance and nutritional status

  • Labs (albumin, total protein, liver function enzymes, INR, bilirubin, serum creatinine or creatinine clearance, thyroid status, and electrolyte abnormalities)

  • Smoking and alcohol history

Specimen information

  • Time of collection

  • Source of specimen: blood, urine, or other body fluid site of collection

  • Order of sample, if part of a series

  • Type of collection tube

  • Time of receipt by laboratory

Laboratories often retain samples for several days and detailed information will help to find a sample if important pre, post, or random samples are needed; the time of collection relative to the dose is extremely important for proper interpretation (Close to a trough? Closer to a peak?); knowing the type of collection tube is important because of the many interferences that may occur; it is important to know the collection site relative to the administration site, if an IV route is used; if a series of samples is to be drawn, the labeled timing of the collection tubes can get mixed up

Drug information

  • Name of drug to be assayed

  • Current dosage regimen, including route

  • Type of formulation (sustained-release, delayed-release, or prompt-release)

  • Length of time on current regimen

  • Time of last dose

  • Concurrent drug therapy

  • Duration of IV infusion

It is important to know if the concentration was drawn at a steady state and when the concentration was drawn relative to the last dose; it is also important to know if there are any potential drug interferences with the assay to be used

Drug concentration history

  • Dates and times of prior concentration measurements

  • Response and drug regimen schedules associated with prior concentrations

It is important to know what drug concentrations have been documented as effective or associated with toxicity; it is also important to know how drug concentrations have changed as a consequence of dosage regimen

Purpose of assay and urgency of request

  • Therapeutic confirmation

  • Suspected toxicity

  • Anticipated inefficacy or toxicity due to change in physiologic/health status or drug–drug interaction

  • Identification of drug failure

  • Suspected overdose

This forces the clinician to have a specific clinical question in mind before ordering a sample; it also aids in the interpretation of results

GI = gastrointestinal;

INR = International Normalized Ratio.

Source: Adapted with permission from references 16 and 17.

Accuracy and completeness of the information provided on a laboratory request form are particularly important in light of the many problems that can occur during the therapeutic drug monitoring process. A drug concentration that seems to be illogical, given the information provided on the form, may be explained by a variety of factors, as shown in Table 5-2 (Minicase 1).

TABLE 5-2.

Common Reasons Why Drug Concentration Results Do Not Make Sense

CATEGORY OF FACTOR

SPECIFIC EXAMPLES

Related to drug administration or blood sampling logistics

  • Wrong dose or infusion rate administered

  • Dose skipped or infusion held for a period of time

  • Dose given at time other than recorded; blood drawn as ordered

  • Dose given at right time; blood drawn at time other than recorded

  • Sample taken through an administration line, which was improperly flushed prior to sample withdrawal

  • Sample taken from the wrong patient

  • Improper or prolonged storage prior to delivery to laboratory

  • Wrong collection tube/device used

  • Patient was dialyzed between doses

Related to pharmacokinetics

  • Sample is drawn prior to steady-state attainment

  • Orders for digoxin samples are not clearly specified to be drawn at least 6 hours postdistribution

  • Samples are ordered at the wrong times relative to last dose to reflect specific needs (eg, peaks and troughs)

  • Concentrations of active metabolites are not ordered when appropriate

  • Concentrations for total drug are ordered for a drug with unusual serum protein binding without recognition that the usual therapeutic range of total drug will not apply

  • Samples after IV administration are drawn prior to completion of distribution phase (eg, vancomycin, aminoglycosides)

Related to the laboratory

  • The wrong drug is assayed

  • Critical active metabolites are not assayed

  • Interferences or artifacts caused by endogenous substances (bilirubin, lipids, and hemolysis) or concurrent drugs

  • Improper or prolonged storage prior to assay

  • Technical errors with the assay

Related to the patient

  • Patient does not adhere to therapy

  • Taking interacting medications that may increase or decrease a drug’s concentration

  • Patient-specific laboratory parameters important for a drug’s pharmacokinetic profile are altered (eg, albumin)

Source: Adapted with permission from references 17 and 25.

Considerations for Appropriate Interpretation of Drug Concentrations

To appropriately interpret a drug concentration, it is important to have as many answers as possible to the following questions:

  • Therapeutic range. What do the studies show to be the usual therapeutic range? How frequently will patients show response at a concentration below the lower limit of the usual range? How frequently will patients show toxicity at a concentration above or even below the upper limit of the usual range? What are the usual signs and symptoms indicating toxicity?

  • Sample timing. Was the sample drawn at a steady state? Was the sample drawn at a time during the dosing interval (if intermittent therapy) that reflects the intended indication for monitoring (a peak, a trough, a “random” concentration, or an average concentration)? During the dosing interval, when is a peak concentration most likely to occur for the formulation administered? Does the formulation exhibit a lag time for release, absorption, or distribution such that the lowest concentration will occur into the next dosing interval?

  • Use of concentrations for dose adjustment. Does the drug display first-order (linear) pharmacokinetic elimination behavior such that an increase in daily dose will produce a proportional increase in the average drug concentration? Will more complex adjustment methods be needed for drugs that display nonlinear elimination behavior? Is the dosage adjustment method focused on attaining specific peaks, troughs, or specific average concentrations?

  • Protein binding, active metabolites, and other considerations. How are total drug concentrations in serum interpreted in cases of altered serum protein binding? How are concentrations or contributions of active metabolites considered along with parent drug? Is the drug administered as a racemic mixture and if so, do the enantiomers differ in activity and pharmacokinetic behavior? Do certain physiologic or pathologic conditions affect a patient’s response to the drug at a given concentration?

Each of these categories is described in general in the section that follows and, more specifically, for each drug or drug class in the Applications section.

THE THERAPEUTIC RANGE

The therapeutic range is also known as the “therapeutic window,” “therapeutic reference range,” “optimal plasma concentration,” and “target range.” The therapeutic range is best defined as “ranges of drug concentrations in blood that specify a lower limit below which a drug induced therapeutic response is relatively unlikely to occur and an upper limit above which tolerability decreases or above which it is relatively unlikely that therapeutic improvement may be still enhanced.” 1,2426 Therapeutic reference ranges are population-based averages for which most patients are expected to respond with acceptable side effects. Thus, there will always be some patients who exhibit therapeutic effect at drug concentrations below the lower limit, while others will experience unacceptable toxicity at concentrations below the upper limit. Therefore, a patient’s therapy is always best guided by a patient’s individual therapeutic concentration and correlated clinical response. It may be most beneficial to measure drug concentrations when a patient has attained the desired clinical response and establish the obtained drug concentration as the optimal concentration for an individual patient.25,26

Figure 5-1 illustrates how the probability of response and toxicity increases with drug concentration for a hypothetical drug and how a therapeutic range might be determined based on these relative probabilities. Figure 5-2 shows how patterns for response and toxicity can change in two different patients receiving the same drug. If the hypothetical drug in question has an active metabolite that accumulates more than the parent drug in renal impairment and if that metabolite contributes more to toxicity than to efficacy, then the individual therapeutic range in the patient with renal impairment will be narrower. Concentration monitoring of the active metabolite would be especially important in that situation.

FIGURE 5-1.
FIGURE 5-1.

The therapeutic range for a hypothetical drug. Line A is the percentage of patients displaying a therapeutic effect; line B is the percentage of patients displaying toxicity.

FIGURE 5-2.
FIGURE 5-2.

Representation showing how the individual therapeutic range of a hypothetical drug can differ in a patient with renal impairment because of accumulated active metabolite.

Drug concentration monitoring is often criticized by claims that therapeutic ranges are not sufficiently well defined.10,11 The lack of clearly defined therapeutic ranges for older drugs is partially attributable to how these ranges were originally determined. Eadie describes the process that was typically used for determination of the therapeutic ranges of the antiepileptic drugs: “These ranges do not appear to have been determined by rigorous statistical procedures applied to large patient populations. Rather, workers seem to have set the lower limits for each drug at the concentration at which they perceived a reasonable (although usually unspecified) proportion of patients achieved seizure control, and the upper limit at the concentration above which overdosage-type adverse effects appear to trouble appreciable numbers of patients, the values then being rounded off to provide a pair of numbers, which are reasonably easy to remember.”14 In an ideal world, studies to define therapeutic ranges for drugs should use reliable methods for measurement of response and should be restricted to patients with the same diseases, age range, and concurrent medications.1 In recent years, the U.S. Food and Drug Administration (FDA) has recognized the importance of determining concentration versus response relationships early during clinical trials.27

Anything that affects the pharmacodynamics of a drug, meaning the response at a given drug concentration, affects the therapeutic range, including the following factors:

  • Indication. Drugs that are used for more than one indication are likely to be interacting with different receptors. Thus, a different concentration versus response profile might be expected depending on the disease being treated. For example, higher serum concentrations of digoxin are needed for treatment of atrial fibrillation as compared with heart failure. Higher antibiotic drug concentrations may be needed for resistant organisms or to penetrate specific infected tissue sites.

  • Active metabolites. As shown in Figure 5-2, variable presence of an active metabolite can shift the therapeutic range for that individual patient up or down. These metabolites may behave in a manner similar to the parent drug or may interact with different receptors altogether. In either case, the relationship between parent drug concentration and response will be altered.

  • Concurrent drug treatment. In a manner similar to active metabolites, the presence of other drugs that have similar pharmacodynamic activities will contribute to efficacy or toxicity but not to measurement of the drug concentration. The therapeutic range will be shifted.

  • Patient’s age. While there is limited information concerning developmental changes in pharmacodynamics in the pediatric population, it is understood that the numbers and affinities of pharmacologic receptors change with progression of age, particularly into advanced age.28 Age-related changes in pharmacodynamics and pharmacokinetics would be expected to result in a shift of the therapeutic range.

  • Electrolyte status. Electrolytes play a critical role in cardiac function and therefore may affect the pharmacodynamics of a given drug. As an example, hypokalemia, hypomagnesemia, and hypercalcemia are all known to increase the cardiac effects of digitalis glycosides and enhance the potential for digoxin toxicity at a given serum concentration.29

  • Concurrent disease. Some disease states may alter the pharmacodynamics and, in some cases, the pharmacokinetics of a given drug and subsequently alter the therapeutic range. As an example, patients with underlying heart disease (cor pulmonale, coronary artery disease) have increased sensitivity to digoxin.29

  • Variable ratios of enantiomers. Some drugs are administered as racemic mixtures of enantiomers, which may have different response/toxicity profiles as well as pharmacokinetic behaviors. Thus, a given concentration of the summed enantiomers (using an achiral assay method) is associated with different concentrations of response or toxicity in patients with different proportions of the enantiomers. This has been extensively studied for disopyramide.30

  • Variable genotype. There is growing evidence that response to certain drugs is genetically determined. For selected drugs, patients may be genotyped before starting drug treatment to identify them as nonresponders, responders, or toxic responders (see Chapter 6).3133 One such drug is bupropion, for which wide patient variability in response is associated with genetic polymorphisms of CYP2B6.34

  • Variable serum protein binding. Theoretically, only the unbound concentration of drug in blood is capable of establishing equilibrium with pharmacologic receptors, thus making it a better predictor of response than total drug concentration. Most drug concentrations in serum, plasma, or blood, however, are measured as the summed concentration of bound and unbound drug. It is likely that some of the patients who show toxicity within the conventional therapeutic range have abnormally low protein (eg, albumin) binding and high concentrations of an unbound drug in blood.35 Low protein binding of a drug in blood can be the result of either reduced protein concentrations or the presence of other substances in blood that displace the drug from protein binding sites. Phenytoin would be an example of a drug requiring consideration of plasma proteins in evaluation of serum concentrations.

Importance of Documenting Drug Administration Times

Michael T., an 86-year-old man (95 kg, 178 cm, baseline SCr 0.78), is receiving vancomycin monotherapy for treatment of a gram-positive bacteremia (unknown source). According to the medical chart, he receives four doses of vancomycin 2,000 mg q 12 h infused over 2 hours on a schedule of 7 a.m./7 p.m. The estimated/predicted half-life of vancomycin in Michael T. based on estimated creatinine clearance is 6 hours. A concentration drawn at 6 a.m. the following morning is reported as 16 mg/L. Based on the current information, the regimen of vancomycin 2,000 mg q 12 h is continued. A repeat concentration 3 days later at 6:30 a.m. reveals a vancomycin trough concentration of 27 mg/L. Renal function, as indicated by creatinine clearance, has not changed in this patient. The pharmacist receives a call to assess and interpret this concentration. If accurate, a dosage adjustment will be necessary to avoid toxicities.

QUESTION: What are the possible explanations for apparent changes in serum vancomycin results? Which vancomycin concentration accurately reflects the current dosage regimen?

DISCUSSION: For any drug requiring therapeutic drug monitoring, one must first consider whether the concentrations accurately represent a steady state. With an estimated vancomycin half-life of 6 hours, a steady state should have been reached after four doses or 48 hours. Because vancomycin depends greatly on the kidney for elimination, a second consideration would be renal function. Of note, this patient’s creatinine clearance is unchanged. Laboratory errors or assay interference/artifacts could lead to difficulty in interpretation of serum drug concentrations. In the case of aminoglycosides, for example, coadministration of piperacillin–tazobactam may lead to in vitro inactivation, which may lead to falsely subtherapeutic concentrations. However, no such interferences were noted for vancomycin in this case. Finally, it is important to confirm the accuracy of blood sampling or drug administration times. After investigating this patient’s medication administration record further, it is discovered that his third vancomycin dose was held, and no adjustment to timing of orders was performed. For this reason, the measured concentration of 16 mg/L was in fact 24 hours after the last dose and therefore did not reflect a true 12-hour trough on the 2,000 mg q 12 h regimen. After analysis of subsequent administration times and doses of vancomycin, the dose is adjusted to 2,000 mg q 24 h. If the first measured concentration had been initially noted to be drawn 24 hours after the previous dose, the clinician could have predicted an elevated vancomycin concentration on the every-12-hour regimen, and a dose adjustment would have been made at that time.

In summary, the therapeutic range reported by the laboratory is only an initial guide and not a guarantee of desired clinical response in any individual patient. Every effort must be made to consider other signs of clinical response and toxicity in addition to the drug concentration measurement. Therapeutic ranges for the most commonly monitored drugs discussed in the Applications section of this chapter are reported in Table 5-3.

TABLE 5-3.

Data to Aid Interpretation of Concentrations of Drugs That Are Commonly Monitored

RECOMMENDED CONCENTRATIONS

RECOMMENDED TIMING

CONSIDERATIONS FOR INTERPRETATION: PROTEIN BINDING, ACTIVE METABOLITES, OTHER FACTORS

Bronchodilators

Theophylline

Adult: 5–15 mg/L

Child: 5–10 mg/L

Neonate: 5–10 mg/L

Trough or Css,avg steady state occurs in 24 hr for an average adult nonsmoker receiving a maintenance infusion, but may take longer for sustained-release products

Concentrations up to 20 mg/L may be necessary in some patients; the caffeine metabolite is of minor significance in adults but may contribute to effect in neonates; theophylline has been replaced by safer bronchodilators in children, and by caffeine in neonates

Antiepileptics

Carbamazepine

4–12 mg/L

Trough or Css,avg steady state may require up to 2–3 wk after initiation of full dose rate due to autoinduction

Lower total concentrations may be more appropriate in patients with decreased protein binding (liver disease, hypoalbuminemia, and hyperbilirubinemia), or in patients taking other anticonvulsants

Phenobarbital

10–40 mg/L

Anytime during interval; steady state may require up to 3 wk

Many drug interactions; consider impact on concentration when starting/stopping interacting medications

Phenytoin

Based on total phenytoin concentrations:

Adult: 10–20 mg/L

Infant: 6–11 mg/L

Neonate: 8–15 mg/L

Trough or Css,avg steady state may require up to 3 wk

Measurement of unbound phenytoin concentrations (therapeutic range of 1–2 mg/L) may be preferred in most patients; lower total phenytoin concentrations may be more appropriate in patients with decreased protein binding due to hypoalbuminemia (eg, liver disease, nephrotic syndrome, pregnancy, cystic fibrosis, burns, trauma, malnutrition, AIDS, and advanced age), ESRD, concurrent use of salicylic acid or VPA

Valproic Acid (VPA)

Epilepsy: 50–100 mg/L (total)

Mania: 50–125 mg/L (total)

Trough or Css,avg

Steady state may require up to 5 days

Lower total VPA concentrations may be more appropriate in patients with hypoalbuminemia (liver disease, cystic fibrosis, burns, trauma, malnutrition, and advanced age), hyperbilirubinemia, ESRD, and concurrent use of salicylic acid; VPA shows interpatient variability in unbound fraction because of nonlinear protein binding; total concentrations increase less than proportionately with increases in daily dose, while unbound concentrations increase proportionately

Antimicrobial Drugs

Amikacin

Traditional dosing:

Peaks: 20–30 mg/L

Troughs: < 8 mg/L

Traditional dosing: steady state should be based on estimated half-life, particularly in patients with renal impairment

Extended-interval dosing: per institution specific protocol (consider two-point and patient-specific kinetics)

Desired peak will depend on infection site (ie, high inoculum infections necessitating higher peaks)

Gentamicin, tobramycin

Traditional dosing:

Peaks: 6–10 mg/L

Troughs: < 1–2 mg/L

Traditional dosing: steady state should be based on estimated half-life, particularly in patients with renal impairment

Extended-interval dosing: per institution specific protocol (consider two-point and patient-specific kinetics)

Desired peak depends on infection site (ie, high inoculum infections necessitating higher peaks)

Vancomycin

AUC-guided monitoring for serious MRSA infections:

>400–600 mg × hr/L

Troughs/traditional based monitoring: 10–20 mg/L

AUC-guided monitoring: one concentration obtained at 1–2 hr postinfusion (Cmax) and a second concentration obtained at the end of dosing interval (trough, Cmin) once steady state is reached; if using Bayesian software, may obtain trough concentration (at end of dosing interval) only; can be drawn prior to reaching steady state

Trough-based monitoring: Concentration within 30 min to 1 hr of next dose; steady state may require up to 2–3 days in patients with normal renal function

AUC-guided monitoring is reserved for invasive MRSA infections; there is not enough data to assess which monitoring approach (AUC-guided vs. trough-only monitoring) should be followed in noninvasive MRSA or other infections

Antifungal Agents

Itraconazole

Trough concentration >0.5–1 mg/L

Concentration can be drawn at any time during a dosing interval once steady state is reached

Variability in absorption and concentrations noted between different formulations (eg, oral capsules versus oral solution)

Posaconazole

Trough >1 mg/L

Concentration can be drawn at any time during dosing interval once steady state is reached at end of first week of therapy

Variability in absorption and concentrations noted between different formulations (eg, oral tablets versus oral suspension)

Voriconazole

Lower limit: >1 mg/L

Upper limit: <4–6 mg/L

Trough concentration (eg, prior to next dose) within first week of therapy initiation or dosage adjustments

Steady state may be reached in 1–2 days; however, it is recommended to wait at least 5 days to measure trough concentration

Cardiac Drugs

Digoxin

0.5–1.2 mcg/L

NEVER sooner than 6 hr after an oral dose; steady state may require up to 7 days with normal renal function

Toxicity more likely within therapeutic range in patients with hypokalemia, hypomagnesemia, hypercalcemia, underlying heart disease, and hypothyroidism; patients with hyperthyroidism may be resistant at a given digoxin concentration, drug interactions

Cytotoxic Drugs

Methotrexate

Therapeutic levels: variable

High-dose regimen:

0.1–1 µM/L

Low-dose regimen:

<0.2 µM/L

Per protocol for determination of leucovorin rescue regimen

Decreased protein binding is observed in some situations, but implications for interpretation of total concentrations are unclear

Immunosuppressant Drugs

Cyclosporine

100–500 mcg/L (whole blood, using specific assay)

Trough or 2-hr after dose; steady state may require up to 5 days

Highly variable unbound fraction in blood; higher total concentrations may be acceptable in patients with hypercholesterolemia or prior to acute rejection episodes (increased serum binding); lower total concentrations might be acceptable in patients with decreased binding in serum (low cholesterol)

Tacrolimus

Initiation: 20 mcg/L

Maintenance: 5–10 mcg/L

Goal concentrations may be patient and institution specific

Trough concentrations three times a week initially until concentrations are stabilized; monitoring intervals can be extended with maintenance therapy

Therapeutic range may shift slightly with concomitant immunosuppressant medications and by indication; many drug interactions; consider impact on concentration when starting/stopping interacting medications

Psychotropics

Lithium

Acute management:

0.5–1.2 mEq/L

Maintenance:

0.6–0.8 mEq/L

12 hr after the evening dose on BID or TID schedule; steady state may require up to 1 wk

Monovalent cation, which is not bound to plasma proteins; does not undergo metabolism

SAMPLE TIMING

Incorrect timing of sample collection is the most frequent source of error when therapeutic drug monitoring results do not agree with the clinical picture.23,36 Warner reviewed five studies in which 70% to 86% of the samples obtained for therapeutic drug monitoring purposes were not usable. In most cases, this was the result of inappropriate sample timing, including lack of attention to the time required to reach a steady state.23 There are two primary considerations for sample timing: (1) how long to wait after initiation or adjustment of a dosage regimen and (2) when to obtain the sample during a dosing interval.

At Steady State

When a drug regimen (a fixed dose given at a regularly repeated interval) is initiated, concentrations are initially low and gradually increase until a steady state is reached. Pharmacokinetically, steady state is defined as the condition in which the rate of drug entering the body is equal to the rate of its elimination. For therapeutic drug monitoring, a steady state means that drug concentrations have leveled off at their highest and, when given as the same dose at a fixed interval, the concentration versus time profiles are constant from interval to interval. This is illustrated in Figure 5-3 for a continuous infusion and a chronic intermittent dosage regimen.

FIGURE 5-3.
FIGURE 5-3.

Concentration versus time plots for a constant infusion and intermittent therapy after initiation of therapy, without a loading dose. The half-life for this hypothetical drug is 8 hours. Thus, 88% of the eventual average steady-state concentration (Css,avg) is attained in 24 hours.

Drug concentration measurements should not be made until the drug is sufficiently close to a steady state so that the maximum benefit of the drug is ensured. The time required to reach a steady state can be predicted if the drug’s half-life is known, as shown here:

NUMBER OF HALF-LIVES

PERCENTAGE OF STEADY STATE ATTAINED

2

75%

3

88%

4

94%

5

97%

This means the clinician should wait three half-lives at a minimum before obtaining a sample for monitoring purposes. The clinician also should anticipate that the “usual” half-life in a given patient may actually be longer due to impaired elimination processes, and it may be prudent to wait longer if possible. The half-lives of drugs that are typically monitored are reported in the Applications section, and typical times to steady state are reported in Table 5-3.

Sometimes drugs are not given as a fixed dose at a fixed interval, or they may undergo diurnal variations in pharmacokinetic handling.37,38 Although the concentration-versus-time profiles may differ from each other within a given day, the patterns from day to day will be the same if steady state has been attained. In cases of irregular dosing or diurnal variations, it is important that drug concentration measurements on different visits be obtained at similar times of the day for comparative purposes.

An unusual situation is caused by autoinduction, as exemplified by carbamazepine. The half-life of carbamazepine is longer after the first dose but progressively shortens as the enzymes that metabolize carbamazepine are induced by exposure to itself.39 The half-life of carbamazepine during chronic therapy cannot be used to predict the time required to reach a steady state. The actual time to reach a steady state is somewhere between the time based on the first-dose half-life and that based on the chronic-dosing half-life. For this reason, patients are typically started on 25% to 33% of the target total daily dose.40 Autoinduction has been found to be reversible when carbamazepine is held for 6 or more days.41

It is a common misconception that a steady state is reached faster when a loading dose is given. Although a carefully chosen loading dose will provide desired target concentrations after the first dose, the resulting concentration is only an approximation of the true steady-state concentration, and it will still require at least three half-lives to attain a true steady state. Whenever possible, it is best to allow more time for a steady state to be attained than less. This is also important because the average half-life for the population may not apply to a specific patient.

There are some exceptions to the rule of waiting until a steady state is reached before sampling. If there is suspected toxicity early during therapy, a drug concentration measurement is warranted and may necessitate immediate reduction or suspension of a dose. Dosing methods designed to predict maintenance dosage regimens using pre–steady-state drug concentrations are useful when rapid individualization of the dosage regimen is needed.4247 For example, a pre–steady-state concentration may be warranted for patients with poor renal function receiving vancomycin in whom supratherapeutic drug concentrations are more likely to occur and cause adverse drug effects.

Within the Dosing Interval

Figure 5-3 shows typical concentration versus time profiles for a drug given by continuous infusion and a drug given by oral intermittent dosing. Once a steady state is attained, drug concentrations during a continuous infusion remain constant, and samples for drug concentration measurements can be obtained at any time. When a drug is given intermittently, however, there is fluctuation in the drug concentration profile. The lowest concentration during the interval is known as the steady-state minimum concentration, or the trough. The highest concentration is known as the steady-state maximum concentration, or the peak. Also shown in Figure 5-3 is the steady-state average concentration (Css,avg), which represents the time-averaged concentration during the dosing interval. An important principle of dosing for drugs that show first-order behavior is that the average concentration during the interval or day will change in direct proportion to the change in the daily dose. This is covered in more detail in the Use of Concentrations for Dosage Adjustment section.

The degree of fluctuation within a dosing interval depends on three factors: the half-life of the drug in that patient; how quickly the drug is absorbed (as reflected by the time at which a peak concentration occurs for that particular formulation); and the dosing interval. The least fluctuation (lowest peak:trough ratio) occurs for drugs with relatively long half-lives that are slowly absorbed or given as sustained-release formulations (prolonged peak time) in divided doses (short dosing interval). However, drugs with relatively short half-lives that are quickly absorbed (or given as immediate-release products) and given only once daily show the greatest amount of fluctuation within the interval.

The choice of timing for samples within the dosing interval should be based on the clinical question to be addressed. Troughs are usually recommended for therapeutic confirmation, especially if the therapeutic range was formulated based on trough concentrations as is the case for most of the antiepileptic drugs (AEDs).14 Trough concentrations are also recommended if the indication for concentration monitoring is avoidance of inefficacy (or in case of certain antimicrobials, development of antimicrobial resistance) or distinguishing nonadherence from therapeutic failure. Trough concentrations should also be monitored if the patient tends to experience symptoms of inefficacy before the next dose (in which case a shortening of the dosing interval might be all that is needed). Although it is logical to assume that the lowest concentration during the interval will occur immediately before the next dose, this is not always the case. Some products are formulated as delayed-release products (eg, enteric-coated valproic acid [VPA]) that are designed to be released from the intestine rather than the stomach. As such, they may not begin to be absorbed for several hours after administration, and the concentration of drug from the previous dose continues to decline for several hours into the next interval. It is important to recognize that the predose concentration for those formulations is not the lowest concentration during the interval (Figure 5-4).

FIGURE 5-4.
FIGURE 5-4.

Concentration versus time profiles for a prompt-release formulation that exhibits a lag time in its release or absorption (delayed-release) as compared with a sustained-release formulation without lag time. Note that the lowest concentration during the dosing interval for the delayed-release product occurs at a time that is typically expected for the peak to occur.

Peak concentrations are monitored less often for drugs given orally because the time at which peak concentrations occur is difficult to predict. If a peak concentration is indicated, the package insert should be consulted for time to peak concentration of individual products. Peak concentration monitoring would be appropriate if the patient complains of symptoms of toxicity at a time believed to correspond with a peak concentration or in some cases correspond to clinical efficacy. Peaks may also be used for intravenous (IV) drugs (eg, aminoglycosides) because the time of the peak is known to correspond to the end of the infusion. For aminoglycosides, the peak concentration is believed to be a predictor of efficacy.48

Sometimes the clinician wishes to get an idea of the average concentration of drug during the day or dosing interval. This is particularly useful when the concentration is to be used for a dose adjustment. Pharmacokinetically, the average concentration equals the area under the curve (AUC) during the dosing interval (requiring multiple samples) divided by the interval. (Note: the AUC during an interval or portion of an interval is used as the monitoring parameter in place of single drug concentration measurements for certain drugs, such as some immunosuppressant and cytotoxic drugs, because it provides a better indication of overall drug exposure.) However, determination of the AUC, or Css,avg, by multiple sampling is not cost-effective for the most commonly monitored drugs. The following alternatives aid in estimating the Css,avg without multiple samples:

  • Look up the expected time to reach a peak concentration for the particular formulation and obtain a sample midway between that time and the end of the dosing interval.24

    Measure the trough concentration (as close to the time of administration of the next dose as possible) and use that along with the population value for the drug’s volume of distribution (Vd) to estimate the peak concentration (in the following equation). Then take the average of the trough and the peak to get an estimate of the average steady-state concentration.
    Peaksteadystate=Dose/Vd+measured trough
  • If you have reason to believe that there is little fluctuation during the dosing interval, then a sample drawn any time during the interval provides a reasonable reflection of the average concentration.

There are special and extremely important timing considerations for some drugs, such as digoxin. It must reach specific receptors, presumably in the myocardium, to exhibit its therapeutic effect, but this takes several hours after the dose is administered. Early after a digoxin dose, concentrations in serum are relatively high, but the response is not yet evident because digoxin has not yet equilibrated at its site of action. Thus, only digoxin concentrations that are in the postdistribution phase should be monitored and compared with the reported therapeutic range (Minicase 2).

The timing of samples for other drugs may be based on the requirements for certain dosing methods. This is true for aminoglycosides and certain lithium dosing methods. Sample timing for drugs such as methotrexate is specified in protocols because concentrations are used to determine the need for rescue therapy with leucovorin to minimize methotrexate toxicity.

Importance of Sample Timing for Digoxin

Ruth D., a 93-year-old female patient with heart failure, coronary artery disease, and diabetes mellitus type 2, was recently discharged from the hospital after a heart failure exacerbation that resulted from new-onset atrial fibrillation with rapid ventricular response. During the hospital stay, the patient received IV doses of metoprolol; however, the patient’s heart rate remained elevated in the 130s and the decision was made to initiate digoxin upon admission. The patient received a loading dose of digoxin 250 mcg IV every 6 hours for three doses followed by 0.25 mg orally once daily at 9:00 a.m. The patient has arrived for her follow-up cardiology appointment. She reports nausea, vomiting, and a loss of appetite for the past several days. On presentation, she is also noted to have some bradycardia. Because of concern for possible digoxin toxicity, the cardiology nurse practitioner ordered a digoxin concentration and basic metabolic panel at 11:30 a.m., which resulted the following results:

  • Digoxin: 3.4 mcg/L

  • Serum creatinine: 0.8 mg/dL

  • Potassium: 3.8 mmol/L

  • Magnesium: 1.9 mg/dL

  • Calcium: 9.1 mg/dL

The cardiology nurse practitioner calls the clinical pharmacy specialist for assistance with digoxin dose adjustment. Ruth D.’s renal function is stable and there have been no medication changes since her discharge last week.

QUESTION: Are there other possible causes for the patient’s GI symptoms? What considerations should be taken into account in the interpretation of this patient’s digoxin concentration? What recommendation should be made at this time?

DISCUSSION: Several non–drug-related reasons for the patient’s GI symptoms are possible, including infection, constipation, acid reflux, and stress, among others that should be considered in addition to digoxin toxicity. There are no new medications; therefore, drug interactions may be ruled out as an explanation for the high digoxin concentration. Digoxin concentrations, with maintenance therapy, should be drawn just prior to the administration of the next dose (trough concentration) or no sooner than 6 to 8 hours after the dose was administered. Her digoxin concentration in serum, however, was drawn 2.5 hours after her 9:00 a.m. dose and therefore does not yet reflect the concentration of digoxin at its myocardial target. To determine if digoxin is the primary cause of her GI symptoms and concomitant bradycardia, a repeat concentration should be drawn after 3:00 p.m. today to account for the distribution of digoxin to tissues. Changes to the medication regimen should be based on the correctly drawn concentration.

Although samples for drug concentration measurements may be preferred at certain times during a dosing interval, visits to physician offices often do not coincide with desired times for blood draws. One is then faced with the matter of how to interpret a concentration that is drawn at a time that happens to be more convenient to the patient’s appointment. The most critical pieces of information to obtain in this situation are (1) when the last drug dose was taken, (2) adherence, (3) timing of the sample relative to the last dose, and (4) the expected time of peak concentration. Some drugs are available as a wide variety of formulations (solutions, suspensions, immediate-release, and sustained-release or extended-release dosage forms), and the package insert may be the best source of information for the expected peak time. Once again, drugs with relatively long half-lives given as sustained-release or slowly absorbed products in divided doses will have the flattest concentration-versus-time profiles, and concentrations drawn anytime during the interval are going to be similar. However, immediate-release drugs with short half-lives given less frequently will show more fluctuation. Knowing the expected peak time for the formulation in question is especially important for drugs that show more fluctuation during that interval. In that case, one can at least judge if the reported concentration is closer to a peak, an average (if midway between the peak and trough), or a trough.

USE OF CONCENTRATIONS FOR DOSAGE ADJUSTMENT

A chronic intermittent dosage regimen has three components: the dose rate, the dosing interval, and the dose. For the dosage regimen of 240 mg every 8 hours, the dose is 240 mg, the interval is 8 hours, and the dose rate can be expressed as 720 mg/day or 30 mg/hr. The degree of fluctuation between doses is highly influenced by the dosing interval. Dose rate is influenced by both the dose and interval; therefore, any change in the dose or interval will be associated with the corresponding change in the dose rate.

Dosage Adjustments for Linear Behavior

If a drug is known to have first-order bioavailability and elimination behavior after the administration of therapeutic doses, one can use simple proportionality to make an adjustment in the daily dose:

  • If average concentrations are being monitored or estimated, one can predict that the average, steady-state drug concentration will increase in proportion to the increase in total daily dose, regardless of any changes made to the dosing interval.

  • If trough concentrations are monitored and the dosing interval is held constant, the trough concentration will increase in proportion to the increase in daily dose.

  • If trough concentrations are monitored for a drug that exhibits considerable fluctuation during the dosing interval and both the dose and dosing interval will be adjusted, the trough concentration will not be as easy to predict at a new steady state and is beyond the scope of this chapter. If the trough concentration can be used to estimate the Css,avg, as described previously, the Css,avg can be predicted to change in proportion to the change in daily dose.

Sampling after a dosage regimen adjustment, if appropriate, should not be done until a new steady state has been reached. For a drug with first-order behavior, this should take the same time (three half-lives at a minimum) that it did after initiation of therapy with this drug.

Dosage Adjustments for Drugs with Nonlinear Behavior

All drugs show nonlinear elimination behavior if sufficiently high doses are given. Some drugs, however, show pronounced nonlinear (Michaelis-Menten) elimination behavior after doses that produce therapeutic drug concentrations. This means that an increase in the dose of the drug results in a greater-than-proportional increase in the drug concentration. Phenytoin is an example of a drug with this behavior. Theophylline and procainamide also show some degree of nonlinear behavior but only at the higher end of their therapeutic ranges and not enough to require special dosing methods.

Methods have been described to permit predictions of the effect of dose increases for phenytoin using population averages or actual measurements of the parameters that define nonlinearity, namely Vmax (maximum rate of metabolism) and Km (the “Michaelis constant”), but they are beyond the scope of this chapter.49 The most important rule to remember for dosage adjustments of drugs such as phenytoin is to be conservative; small increases in the dose produce unpredictably large increases in the serum drug concentration. It must also be noted that the half-life of a drug like phenytoin is progressively prolonged at higher concentrations. Increases in the dose require a longer period of time to reach a steady state as compared with when the drug was first initiated.

Population pharmacokinetic or Bayesian dosage adjustment methods, which involve the use of statistical probabilities, are preferred by many for computerized individualization of therapy and can be used for drugs with both linear and nonlinear behavior.47,50

PROTEIN BINDING, ACTIVE METABOLITES, AND OTHER CONSIDERATIONS

Altered Serum Binding

Total (unbound plus protein-bound) drug concentrations measured in blood, serum, or plasma are most frequently used for therapeutic drug monitoring, despite the fact that unbound drug concentrations are more closely correlated to drug effect.35 While total concentrations are easier to measure, it should be noted the ratio of unbound to total drug concentration in serum is usually constant within and between individuals. For some drugs, however, the relationship between unbound and total drug concentration is extremely variable among patients, or it may be altered by disease or drug interactions. For drugs that undergo concentration-dependent serum binding, the relationship between unbound and total concentration varies within patients. In these situations, total drug concentration does not reflect the same concentration of activity as with normal binding and must be cautiously interpreted because the usual therapeutic range does not apply (Minicase 3).

The direct measurement of unbound drug concentration would seem to be appropriate in these situations. Drugs for which total concentration monitoring is routinely performed (but for which unbound concentration monitoring has been proposed) include carbamazepine, phenytoin, and VPA. Of these, correlations between unbound drug concentration and response have been weakly established for carbamazepine but more firmly established for phenytoin.35,51,52

Unbound drug concentration measurements involve an extra step prior to analysis—separation of the unbound from the bound drug. If unbound drug concentration measurements are unavailable, too costly, or considered impractical, the following alternative approaches to interpreting total drug concentrations in situations of altered serum protein binding may be used:

  • Use of equations to normalize the measured total concentration. Sheiner and Tozer were the first to propose equations that can be used to convert a measured total concentration of drug (phenytoin in this case) to an approximation of what the total concentration would be if the patient had normal binding.53 Equations to normalize PHT concentrations have been used for patients with hypoalbuminemia, impaired renal function, and concurrent VPA therapy.5456 Once the total concentration has been normalized, it may be compared with the conventional therapeutic range. It must be noted that this normalization method may not be a reliable substitute for the measurement of the unbound phenytoin concentration, particularly when clinical presentation does not correlate with the obtained drug concentration.

  • Normalization of the measured total concentration using literature estimates of the abnormal unbound drug fraction. An alternative method for normalizing the total concentration can be used if reasonable estimates of the abnormal and normal unbound reactions of the drug can be ascertained (ie, from the literature). The normalized total concentration (Cnormalized) can be estimated as
    Cnormalized=Cmeasured×abnormal unbound fractionnormal unbound fraction

where Cmeasured is the measured total concentration reported by the laboratory.

  • Predictive linear regression equations. Some studies have reported the ability to predict unbound drug concentrations in the presence of displacing drugs if the total concentrations of both drugs are known. This has been done to predict unbound concentrations of phenytoin and carbamazepine, both in the presence of VPA.55,56 These unbound drug concentrations should be compared with corresponding therapeutic ranges of unbound drug, which can be estimated for any drug if the normal unbound fraction and the usual therapeutic range of total concentrations are known.

  • Use of saliva as a substitute for unbound drug concentration. Saliva may be a reasonable alternative so long as studies have shown a strong correlation between unbound concentrations in serum and concentrations in saliva. The concentration of drug in saliva may not be equal to the concentration in serum ultrafiltrate; therefore, the laboratory should have determined a reliable conversion factor for this. The calculated unbound concentration may then be compared with the estimated therapeutic range for unbound concentrations as described previously. Saliva concentrations may also be used as a predictor of total drug concentrations, particularly for some of the AEDs.57

  • Active metabolites—Interpretation of parent drug concentration alone, for drugs with active metabolites that are present to varying extents, is difficult at best. Active metabolites may contribute to therapeutic response, toxicity, or both. Because metabolites likely have different pharmacokinetic characteristics, they are affected differently than the parent drug under different physiologic and pathologic conditions. For drugs such as primidone (metabolized to phenobarbital) and procainamide (metabolized to N-acetylprocainamide [NAPA]), the laboratory typically reports both the parent drug and the metabolite as well as a therapeutic range for both. Although a therapeutic range for the sum of procainamide and NAPA may be reported by some laboratories, this practice is discouraged because the parent drug and metabolites have different types of pharmacologic activities.

  • Enantiomeric pairs. Some drugs exist as an equal mixture (racemic mixture) of enantiomers, which are chemically identical but are mirror images of each other. Because they can interact differently with receptors, they may have different pharmacodynamic and pharmacokinetic properties. The relative proportions of the enantiomers can differ widely among and within patients. Thus, a given concentration of the summed enantiomers (what is routinely measured using achiral methods) can represent different activities.31

Value of Unbound Antiepileptic Drug Serum Concentrations

Trevor L., a 26-year-old White man, is discharged after a long inpatient admission following a high-speed vehicle accident, which led to significant brain swelling secondary to a traumatic brain injury. Consequently, he exhibited clinical findings of seizure activity while admitted and it was recommended he be discharged on phenytoin 200 mg TID. Today (4 weeks after discharge) is his follow-up appointment with the neurology department. The patient reveals to the neurologist that he has been experiencing ataxia and dizziness. The neurology resident is concerned about antiepileptic drug toxicity, namely, phenytoin toxicity, and orders a phenytoin total serum concentration, along with a complete metabolic panel as part of routine monitoring.

Results: Phenytoin:

16 mg/L (reference range 10 to 20 mg/L)

Albumin:

1.8 g/dL

Serum creatinine:

0.98 mg/dL

The neurology resident is perplexed given the phenytoin concentration is within therapeutic range and calls the hospital clinical pharmacist to discuss it further.

QUESTION: How is the total concentrations of phenytoin misleading in this case? What further recommendations should the pharmacist provide the resident to determine whether the symptoms the patient is experiencing are related to antiseizure therapy toxicity?

DISCUSSION: Assessing the patient’s symptoms solely on the total phenytoin concentrations can be misleading and can lead to seeking alternative explanations for the patient’s symptoms, thereby delaying necessary life-saving medication dose adjustments.

Phenytoin binds primarily to albumin in plasma. The patient has significant hypoalbuminemia; therefore, interpreting the phenytoin concentrations using total phenytoin only can be misleading and it is expected that the unbound concentration is likely higher than the therapeutic range of unbound concentration of 1 to 2 mg/L. Several approaches can be followed in a situation like this to assist with assessing the patient’s clinical findings: (1) ordering an unbound phenytoin concentration, (2) calculating the unbound phenytoin concentration, or (3) using special equations to convert the phenytoin concentration to what it would be if the patient had normal serum protein binding. One specialized equation is commonly called the Winter-Tozer equation. This equation normalizes phenytoin concentration in patients with hypoalbuminemia.

Corrected phenytoin concentration is as follows:
measured phenytoin/X*albumin+0.1

where X in this patient’s case is 0.25 for low albumin in patients with head trauma.

Corrected phenytoin concentration is as follows:
16mg/L/0.25*1.8g/dL+0.1=29mg/L

The corrected phenytoin concentration reveals a supratherapeutic concentration that is likely contributing to the patient’s current symptoms and complaints.

Table 5-3 provides relevant information about protein binding, active metabolites, and other influences on serum concentration interpretation for drugs discussed in the Applications sections that follow.

APPLICATIONS

Analgesic Drugs

Acetaminophen

Therapeutic range and clinical considerations

Acetaminophen is the first-line treatment for patients with osteoarthritis and mild-to-moderate chronic pain.58,59 Additionally, acetaminophen is a commonly used antipyretic agent.60 Acetaminophen serum concentrations should be monitored only when a suspected or confirmed overdose is a concern or in patients taking long-term acetaminophen with concomitant liver dysfunction.61 Antipyretic activity is expected to occur at serum concentrations of 4 to 18 mg/L; analgesic activity is expected to occur at serum concentrations of 10 mg/L.62 Historically, 4,000 mg/day has long been considered a safe therapeutic dose in normal patients.6365

Sample timing

Acetaminophen serum concentrations should be drawn at least 4 hours after suspected acute ingestion to ensure drug absorption; the Rumack–Matthew nomogram should be referenced to determine treatment decisions.66 In the case of IV formulation overdose, reliable guidelines related to monitoring and management have not been established.

Protein binding, active metabolites, and other considerations

Acetaminophen is 10% to 25% bound to protein at therapeutic concentrations and 8% to 43% at supratherapeutic concentrations.60

Bronchodilators

Aminophylline and Theophylline

Therapeutic range and clinical considerations

Although aminophylline and theophylline are rarely used in practice, serum concentration monitoring may be necessary because of variable pharmacokinetics. These agents are not recommended for the treatment of asthma exacerbations according to the Global Initiative for Asthma 2020 guidelines due to efficacy and safety concerns.67 The 2020 Global Initiative for Chronic Obstructive Lung Disease guidelines recommend using a more effective therapy of inhaled long-acting bronchodilators over theophylline when possible. In the management of chronic obstructive pulmonary disease exacerbations, IV theophylline is not recommended due to significant side effects. Peak concentrations of 5 to 20 mg/L are targeted with concentrations >20 mg/L being associated with adverse events.68,69 There is an 85% probability of adverse effects with concentrations above 25 mg/L; concentrations above 30 to 40 mg/L are associated with dangerous adverse events.70 Many patients do not tolerate theophylline; adverse effects typically experienced by adults include nausea, vomiting, diarrhea, irritability, and insomnia at concentrations above 15 mg/L; supraventricular tachycardia, hypotension, and ventricular arrhythmias at concentrations above 40 mg/L; and seizures, brain damage, and even death at higher concentrations.71

Theophylline is also indicated for treatment of neonatal apnea, although caffeine is preferred.72 The therapeutic range of theophylline in neonates is generally considered to be 5 to 10 mg/L but may be as low as 3 mg/L or as high as 14 mg/L.7376 Adverse effects in neonates include lack of weight gain, sleeplessness, irritability, diuresis, dehydration, hyperreflexia, jitteriness, and serious cardiovascular and neurologic events.70 Tachycardia has been reported in neonates with concentrations as low as 13 mg/L.77

In summary, there is considerable overlap of therapeutic and toxic effects within the usual therapeutic ranges reported for theophylline in neonates, children, and adults. Indications for theophylline monitoring include therapeutic confirmation of effective concentrations after initiation of therapy or a dosage regimen adjustment, anticipated drug–drug interactions, change in smoking habits, and changes in health status that might affect the metabolism of theophylline.

Sample timing

Concentrations should be measured 30 minutes after the end of the infusion if an aminophylline loading dose is given; continuous infusion monitoring should include monitoring serum concentrations at one half-life after the start of the infusion and at every 12 or 24 hours after the start of the infusion.78 The half-life of theophylline can range anywhere from 20 to 30 hours in premature infants to 3 to 5 hours in children or adult smokers to as long as 50 hours in nonsmoking adults with severe heart failure or liver disease.68,73 Steady state is reached in 24 hours for the average patient, with an elimination half-life of 8 hours, but requires a much longer elimination time for patients with heart failure or liver disease. The time to steady state in premature neonates may be as long as 9 days.74

The fluctuation of theophylline concentrations within a steady-state dosing interval can be quite variable, depending not only on the frequency of administration but also on the type of formulation, half-life, and whether the dose was taken with a meal.70,71 Trough concentrations of theophylline are most reproducible and should be used for monitoring. Comparisons of trough concentrations from visit to visit can be facilitated if samples are obtained at the same time of day on each visit due to the diurnal variations in the rate of theophylline absorption.70

Use of concentrations for dosage adjustment

Theophylline is usually assumed to undergo first-order elimination, but some of its metabolic pathways are nonlinear at concentrations at the higher end of the therapeutic range. The clearance of theophylline decreases by 20% as daily doses are increased from 210 mg to 1,260 mg.70 For IV formulations, concentrations should be checked every 24 hours to determine if dose adjustment is warranted; for oral formulations, intervals of 6 to 12 months are recommended once the daily dose has been stabilized.68,79

Protein binding, active metabolites, and other considerations

Theophylline is 35% bound to serum proteins in neonates and 40% to 50% in adults; therefore, significant alterations in serum protein binding are unlikely.79 Theophylline is metabolized to the active metabolite caffeine, which is of minor consequence in adults. Caffeine concentrations in the serum of neonates, however, are approximately 30% of theophylline concentrations and contribute to treatment of neonatal apnea, which may account for the slightly lower therapeutic range of theophylline in neonates as compared with adults.80

Caffeine

Therapeutic range and clinical considerations

Caffeine is indicated for neonatal apnea (apnea of prematurity) and is recommended over theophylline because it can be given once daily (due to a longer half-life), has a wider therapeutic index, and does not require drug concentration monitoring. 72,80 Concentrations as low as 5 mg/L may be effective, but most pediatric textbooks consider 10 mg/L to be the lower limit of the therapeutic range; an acceptable reference range is 8 to 14 mg/L.76,81,82 Toxicity may occur at concentrations >20 mg/L, and serious toxicity is associated with serum concentrations above 50 mg/L. Signs of toxicity include jitteriness, vomiting, irritability, tremor of the extremities, tachypnea, and tonic-clonic movements. Serum concentration measurements of caffeine may not be routinely necessary for apnea of prematurity in neonates.80,83 However, neonates who do not respond as expected or in whom there is recurrence of apnea after a favorable response may benefit.

Sample timing

The half-life of caffeine in preterm infants at birth ranges from 40 to 230 hours.81,82 Thus, a loading dose is always administered to attain effective concentrations as soon as possible. The long half-life means that caffeine concentrations will not fluctuate much during the interval, even when caffeine is administered once daily. Sampling in the postdistribution phase is recommended, which is at least 2 hours after the dose.

Baseline concentrations of caffeine must be obtained prior to the first caffeine dose in the following situations: (1) if the infant had been previously treated with theophylline because caffeine is a metabolite of theophylline and (2) if the infant was born to a mother who consumed caffeine prior to delivery. Reductions in the usual caffeine dose are necessary if predose caffeine concentrations are present.

Use of concentrations for dosage adjustment

No data suggest that caffeine undergoes nonlinear elimination. Thus, dosage adjustments by proportionality are acceptable. Dosage adjustments for caffeine are complicated by the fact that a true steady state is not reached for at least 4 days, so any adjustments should be conservative.

Protein binding, active metabolites, and other considerations

Caffeine is only 31% bound to serum proteins and has no active metabolites.81

Antiepileptic Drugs

Antiepileptic drugs (AEDs) have clearly defined therapeutic ranges for the indication of seizures, unless otherwise stated; however, concentrations associated with toxicity would apply across all indications. Because AEDs are used as prophylaxis for seizures that may not occur frequently, it is particularly important that effective serum concentrations of these drugs be ensured early in therapy. Although AEDs are often only used for prophylaxis, they provide a unique challenge because seizures occur irregularly and unpredictably to be able to correlate clinically with therapeutic drug monitoring. Indications for monitoring AEDs include (1) documentation of an effective steady-state concentration after initiation of therapy, (2) after dosage regimen adjustments, (3) after adding a drug that has potential for interaction, (4) changes in disease state or physiologic status that may affect the pharmacokinetics of the drug, (5) within hours of a seizure recurrence, (6) after an unexplained change in seizure frequency (7) suspected dose-related drug toxicity, and (8) suspected nonadherence.14,84,85

Carbamazepine

Therapeutic range and clinical considerations

Carbamazepine is indicated for the prevention of partial seizures and generalized tonic-clonic seizures as well as the treatment of pain associated with trigeminal neuralgia.73,86 Extended-release formulations have been approved for the prevention and treatment of acute manic or mixed episodes in patients with bipolar I disorder.87 Most textbooks report a therapeutic range of 4 to 12 mg/L. Concentrations above 12 mg/L are most often associated with nausea and vomiting, unsteadiness, blurred vision, drowsiness, dizziness, and headaches in patients taking carbamazepine alone.39 Patients taking other AEDs, such as primidone, phenobarbital, VPA, or phenytoin, may show similar adverse effects at carbamazepine concentrations as low as 9 mg/L. Additionally, some central nervous system (CNS) effects such as drowsiness, dizziness, or headaches can be seen at concentrations >8 mg/L.88 Many clinicians target the lower end of the therapeutic range (4 to 8 mg/L) to avoid adverse effects seen at concentrations of 11 to 15 mg/L (somnolence, nystagmus, ataxia) or toxicities at 15 to 25 mg/L of agitation, hallucinations, and chorea.85,86 Toxicity is expected at concentrations >20 mg/L; serious adverse reactions are seen at concentrations >50 mg/L.89,90

Carbamazepine 10,11-epoxide is an active metabolite that can be present in concentrations containing 12% to 25% carbamazepine, but it is not routinely monitored along with the parent drug. A suggested therapeutic range for this metabolite, used at some research centers, is 0.4 to 4 mg/L; toxicity is expected at concentrations >9 mg/L.73,91

In addition to the usual indications for monitoring, it is important to monitor carbamazepine concentrations if the patient is switched to another formulation (eg, generic) because bioavailability may vary between formulations.85

Sample timing

If a loading dose is administered, concentrations can be taken 2 hours after administration of the suspension formulation to ensure therapeutic concentrations have been achieved.92 Because carbamazepine induces its own metabolism, it is recommended that initial doses of carbamazepine be relatively low and gradually increased over a 3- to 4-week period.39 For maximal induction or deinduction to occur, 2 to 3 weeks may be required after the maximum dose has been attained. Thus, a total of 6 to 7 weeks may be required for a true steady state to be reached after initiation of therapy. After any dose changes or addition/discontinuation of enzyme-inducing or inhibiting drugs, 2 to 3 weeks is required to reach a new steady state.73 It is recommended that during dose titration, carbamazepine concentrations be measured at weekly intervals. After reaching the maintenance dose, blood concentrations can be less frequently monitored at 3- to 6-month intervals.92

A trough concentration is generally preferred. The absorption of immediate-release carbamazepine tablets from the GI tract is relatively slow and erratic, reaching a peak between 3 and 8 hours after a dose.93 Extended-release formulations are even more slowly absorbed. If carbamazepine is administered every 6 or 8 hours, serum concentrations during the dosing interval remain fairly flat, and all concentrations will be fairly representative of a trough concentration. Less frequent dosing results in more fluctuation, in which case the time of the concentration relative to the last dose should be documented for appropriate interpretation. Use of the extended-release formulation of carbamazepine minimizes fluctuations caused by diurnal variations.94 Nevertheless, it is recommended that samples on repeated visits always be obtained at the same time of the day for purposes of comparison.85

Use of concentrations for dosage adjustment

Carbamazepine exhibits nonlinear behavior due to autoinduction, which can lead to an increase in drug elimination.95 An additional 10% to 20% should be added or subtracted for a dose increase or dose decrease, respectively, to account for the autoinduction previously described.96 After the autoinduction period, if the dose is adjusted without a change in the interval, a concentration drawn at the same time within the interval increases in proportion to the increase in dose.

Protein binding, active metabolites, and other considerations

The absorption of carbamazepine is variable after oral ingestion and is formulation dependent.95 In most patients, carbamazepine is 70% to 80% bound to serum proteins, including albumin and α-1-acid glycoprotein (AAG).97 In some patients, however, unbound percentages as low as 10% have been reported. Measurements of unbound carbamazepine concentrations are not generally recommended or necessary. Total concentrations should be carefully interpreted in situations of suspected altered protein binding. Decreased binding might be anticipated in uremia, liver disease, hypoalbuminemia, or hyperbilirubinemia.73 Increased binding might be rarely expected in cases of physiologic trauma due to elevated AAG concentrations. Because VPA has been shown to displace carbamazepine from albumin, an equation was proposed to predict unbound carbamazepine concentrations in this situation.56 Correlations between saliva and unbound carbamazepine concentrations are strong.98 Thus, saliva sampling might be considered in situations of suspected alterations in carbamazepine binding.99

Drug–drug interactions that are expected to result in a higher proportion of active 10,11-epoxide metabolite relative to the parent drug (eg, concurrent phenytoin, phenobarbital, or VPA) may alter the activity associated with a given carbamazepine concentration. It is suggested that a lower therapeutic range of 4 to 8 mg/L be used when those drugs are given concurrently.14 Carbamazepine-10, 11-epoxide is 50% protein bound.100

Phenobarbital/Primidone

Primidone and phenobarbital are both used for the management of generalized tonic-clonic and partial seizures.73 Phenobarbital is also used for febrile seizures in neonates and infants, while primidone is used for treatment of essential tremor.85,101 Although primidone has activity of its own, most clinicians believe that phenobarbital—a metabolite of primidone—is predominantly responsible for primidone’s therapeutic effects.

Therapeutic ranges and clinical considerations

The therapeutic range of phenobarbital for treatment of tonic-clonic, febrile, and hypoxic ischemic seizures is generally regarded as 10 to 40 mg/L, while concentrations as high as 70 mg/L may be required for refractory status epilepticus.85,101 Eighty-four percent of patients are likely to respond with concentrations between 10 and 40 mg/L.101 Management of partial seizures generally requires higher phenobarbital concentrations than management of bilateral tonic-clonic seizures.14 Concentrations of phenobarbital are almost always reported when primidone concentrations are ordered; site-specific laboratory protocols should be followed. The therapeutic range of primidone reported by most laboratories is 5 to 12 mg/L.14,85 Fifteen percent to 20% of a primidone dose is metabolized to the active phenobarbital; the side effects of primidone are mostly related to phenobarbital.73 CNS side effects such as sedation and ataxia generally occur in chronically treated patients at phenobarbital concentrations between 35 and 80 mg/L. Stupor and coma have been reported at phenobarbital concentrations above 65 mg/L.93 Clinicians should consider drawing concentrations when nonadherence or toxicity is suspected if the patient is experiencing lack of efficacy, in patients with severe liver or kidney disease (including dialysis), and when interacting medications are initiated or discontinued.102

Sample timing

The half-life of phenobarbital is the rate limiting step for determining the time to reach steady state after primidone administration. The half-life of phenobarbital averages 5 days for neonates and 4 days for adults.101 Because phenobarbital or primidone dosage may be initiated gradually, steady state is not attained until 2 to 3 weeks after full dosage has been implemented. Because of phenobarbital’s long half-life, concentrations obtained anytime during the day would provide reasonable estimates of a trough concentration. Ideally, concentrations should be obtained from visit to visit at similar times of the day.101 If IV phenobarbital is administered, serum concentrations should be drawn at least 1 hour postinfusion.103

Use of concentrations for dosage adjustment

Phenobarbital and primidone exhibit linear elimination behavior; thus, a change in the dose of either drug will result in a proportional change in average steady-state serum concentrations.93,101

Protein binding, active metabolites, and other considerations

Phenobarbital is approximately 50% bound to serum proteins (albumin) in adults; primidone is not bound to serum proteins.85,104 Thus, total concentrations of both drugs are reliable indicators of the active, unbound concentrations of these drugs. Although primidone has an active metabolite, phenylethylmalonamide, its contribution to activity is unlikely to be significant. Clearance of phenobarbital can increase or decrease depending on many patient-specific factors, including age (decreases in neonates and elderly patients), severe liver or kidney disease (decreases), interacting medications (increases or decreases), urine pH (increases), and malnutrition (increases).105111 Salivary phenobarbital concentrations correlate well with both plasma total and free phenobarbital concentrations, making salivary concentrations a useful alternative in therapeutic drug monitoring.95

Phenytoin and Fosphenytoin

Therapeutic range

Phenytoin is primarily used for treatment of generalized tonic-clonic and complex partial seizures.112 It may also be used in the treatment of trigeminal neuralgia and seizure prophylaxis after neurosurgery.73,112 Studies have shown that serum concentrations of phenytoin between 10 and 20 mg/L result in maximum protection from primary or secondary generalized tonic-clonic seizures in most adult patients with normal protein binding. Ten percent of patients with controlled seizures have phenytoin concentrations <3 mg/L; 50% have concentrations <7 mg/L; and 90% have concentrations <15 mg/L. Concentrations at the lower end of the range are effective for bilateral seizures, while higher concentrations appear to be necessary for partial seizures.14 The therapeutic range of total concentrations in infants is lower (6 to 11 mg/L) due to lower serum protein binding. Concentration-related side effects include nystagmus; CNS depression (ataxia, inability to concentrate, confusion, and drowsiness); and changes in mental status, coma, or seizures at concentrations >40 mg/L.85 Although mild side effects may be observed at concentrations as low as 5 mg/L, there have been cases in which concentrations as high as 50 mg/L have been required for effective treatment without negative consequences.113

Some clinicians have proposed that monitoring of phenytoin be limited to unbound concentrations, particularly in patients who are critically ill or likely to have unusual protein binding.52,114,115 Unbound phenytoin concentrations are more predictive of clinical toxicity than are total phenytoin concentrations in these individuals.116 The therapeutic range of unbound phenytoin concentrations is presumed to be 1 to 2 mg/L for laboratories that determine the unbound phenytoin fraction at 25°C, and 1.5 to 3 mg/L if done at 37°C.116

Fosphenytoin is the IV prodrug of phenytoin; fosphenytoin pharmacokinetics and related monitoring are based on phenytoin calculations.117119

Sample timing

The time required to attain steady state after initiation of phenytoin therapy is difficult to predict because of phenytoin’s nonlinear elimination behavior. Although the T50% is approximately 24 hours (considering the average population Vmax and Km values when concentrations are between 10 and 20 mg/L), there can be extreme variations in these population values. Half-lives between 6 and 60 hours have been reported in adults.85 Thus, a steady state might not be attained for as long as 3 weeks. Some clinicians advise that samples be obtained prior to steady state (after 3 to 4 days) to make sure that concentrations are not climbing too rapidly.112 Equations have been developed to predict the time required to reach a steady state once Vmax and Km values are known.49 It is important to recognize that the time required to reach a steady state in a given patient is longer each time the dose is further increased.

Most clinicians advise that trough phenytoin concentrations be monitored.85 Phenytoin is quite slowly absorbed, so that the concentration versus time profile is fairly flat. This is especially true when oral phenytoin is administered two or three times per day. In this case, a serum phenytoin sample drawn any time during the dosage interval is likely to be close to a trough concentration. The greatest fluctuation would be seen for the more quickly absorbed products (chewable tablets and suspension) in children (who have a higher clearance of phenytoin) given once daily. In this case, it is particularly important to document the time of sample relative to the dose to identify if the concentration is closer to a peak, a trough, or a Css,avg.

Use of concentrations for dosage adjustment

Phenytoin exhibits pronounced nonlinear behavior after therapeutic doses. Thus, increases in dose will produce greater-than-proportional increases in the average serum concentration during the dosing interval. Several methods, described elsewhere, use population and patient-specific Vmax and Km values to predict the most appropriate dose adjustment.49 The clinician must be vigilant to limit phenytoin daily dose increases to less than 30 to 60 mg of sodium phenytoin and less than 25 to 50 mg of the chewable tablets.

Protein binding, active metabolites, and other considerations

The metabolites of phenytoin have insignificant activity. Phenytoin binds primarily to albumin in plasma, and the normal unbound fraction of drug in plasma of adults is 0.1.85,112 Lower serum binding of phenytoin is observed in neonates and infants and in patients with hypoalbuminemia, liver disease, nephrotic syndrome, end-stage renal disease (ESRD), pregnancy, cystic fibrosis, burns, trauma, malnourishment, acquired immunodeficiency syndrome (AIDS), and advanced age.73,120 Concurrent drugs (VPA and salicylates) are known to displace phenytoin.73 Therefore, a total concentration of phenytoin that is within the range of 10 to 20 mg/L in these patients might represent an unbound concentration that is higher than the therapeutic range of unbound concentrations of 1 to 2 mg/L. A total concentration of phenytoin in this situation can be misleading. Several approaches can be used in these situations: (1) an unbound phenytoin concentration can be ordered, if available; (2) the patient’s unbound phenytoin concentration can be calculated by estimating the unbound fraction in the patient (using the literature) and multiplying that by the patient’s measured phenytoin concentration (the resulting unbound concentration should then be compared with 1 to 2 mg/L); or (3) special equations may be used to convert the phenytoin concentration to what it would be if the patient had normal serum protein binding.

The following equation, commonly called the Winter-Tozer equation, was developed to normalize phenytoin concentrations in patients with hypoalbuminemia and renal failure and has been revised for use in various patient populations73,112,121123:
normalized PHT concentration = measured PHT concentrationX×albumin concentration,g/dL+0.1

The value “X” is 0.25 for elderly patients or patients with head trauma with low albumin and creatinine clearances ≥25 mL/min; 0.2 for patients with normal or low albumin who are receiving dialysis; and 0.29 for neurocritical care. Additionally, a coefficient of 0.275 has been proposed as having more broad applicability to a variety of patients.124 Total concentrations of phenytoin in patients with creatinine clearance values between 10 and 25 mL/min cannot be as accurately normalized; the clinical status of such patients should be carefully considered because total concentrations can be misleading. The Winter-Tozer equation for normalizing phenytoin concentrations has been tested by groups of investigators in different groups of patients with mixed reviews; it is emphasized that it should be used only as a guide.

Known to increase the unbound fraction of phenytoin in serum, VPA also has been variably reported to inhibit the metabolism of phenytoin.125 These two occurrences together could mean that a concentration within the range of 10 to 20 mg/L is associated with adverse effects and an unbound phenytoin concentration of 2 mg/L. If unbound phenytoin concentrations are not available, the following equations—modified from their original form—may be useful to normalize the phenytoin concentration if the concentration of VPA in that same sample has been measured.54,112 Notably, some controversy remains regarding which equation provides better accuracy and may be dependent on the laboratory method used to obtain the total phenytoin concentration; therefore, clinical judgement should be used when determining which method is most appropriate for a particular situation.54,126

Haidukewych equation55:
Corrected free PHT=0.095+0.001VPATotal PHT
May equation56:
Corrected free PHT=0.0792+0.000636VPATotal PHT

Salivary concentrations of phenytoin are strongly predictive of unbound phenytoin concentrations and have the added advantage of being noninvasive and thus an option for children and elderly patients.57

Valproic Acid

Therapeutic range

In addition to partial and generalized tonic-clonic and myoclonic seizures, VPA is used for management of absence seizures and for a variety of other conditions, including prophylaxis against migraine headaches and bipolar disorder.85 Most laboratories use 50 to 100 mg/L as the therapeutic range for trough total VPA concentrations in the treatment of epilepsy; concentrations of 50 to 125 mg/L are considered therapeutic in the treatment of mania.127 Some patients with epilepsy are effectively treated at lower concentrations, and others may require trough concentrations as high as 120 mg/L.128 Concentrations at the upper end of the therapeutic range appear to be necessary for treatment of complex partial seizures.128 The same therapeutic range has been used for patients with migraines or bipolar disorder, although the value of routine serum concentration monitoring for bipolar disorder has been questioned.129,130 The following concentration-related side effects may be seen: ataxia, sedation, lethargy, and fatigue at concentrations >75 mg/L; tremor at concentrations >100 mg/L; and stupor and coma at concentrations >175 mg/L.128 The therapeutic range of total VPA concentrations is confounded by the nonlinear serum protein binding of this drug, which might explain some of the variable response among and within patients at a given total serum concentration.73

Sample timing

The half-life of VPA ranges between 7 and 18 hours in children and adults and 17 and 40 hours in infants.85 Thus, as long as 5 days may be required to attain a steady state. The pattern of change in VPA concentrations varies from interval to interval during the day because of considerable diurnal variation.85,128 It is, therefore, recommended that samples always be obtained prior to the morning dose as the trough concentration has been shown to be most consistent from day to day.128 Considerable fluctuation within the interval is seen with the immediate-release capsule and syrup, which are rapidly absorbed. The enteric-coated, delayed-release tablet formulation of VPA displays a shift to the right with respect to its concentration-versus-time profile, such that the lowest concentration during the interval may not be observed until 4 to 6 hours into the next dosing interval.93 It is important to know, however, that concentrations during the interval after administration of the enteric-coated tablet show considerable fluctuation. The extended-release formulations, if given in divided doses, provide less fluctuation in concentrations, and samples may be drawn at any time.

Use of concentrations for dosage adjustment

The metabolism of unbound VPA is linear following therapeutic doses. Thus, unbound VPA concentrations increase in proportion to increases in dose.83,93 Because VPA shows nonlinear, saturable protein binding in serum over the therapeutic range, total concentrations increase less than proportionally. This is important to keep in mind when interpreting total VPA concentrations.

Protein binding, active metabolites, and other considerations

VPA is 90% to 95% bound to albumin and lipoproteins in serum. The unbound fraction of VPA shows considerable interpatient variability. It is increased in neonates, in conditions in adults associated with hypoalbuminemia (eg, liver disease, nephrotic syndrome, cystic fibrosis, burns, trauma, malnutrition, and advanced age), and as a result of displacement by endogenous substances (eg, bilirubin, free fatty acids, and uremic substances in ESRD) and other drugs (eg, salicylates).73,130,131 The increase in the unbound fraction of VPA during labor is believed to be the result of displacement by higher concentrations of free fatty acids.132 Intrapatient variability in the unbound fraction exists because of nonlinear binding. The unbound fraction of VPA is fairly constant at lower concentrations but progressively increases as total concentrations rise >75 mg/L.85 Thus, total concentrations do not reflect unbound concentrations at the upper end of the therapeutic range. A therapeutic range for unbound VPA concentrations can only be approximated. Assuming unbound fractions of 0.05 to 0.1 and a therapeutic range of total VPA concentrations of 50 to 100 mg/L, an unbound therapeutic range of 2.5 to 10 mg/L can be deduced.

Other Antiepileptic Drugs

Routine serum concentration monitoring is not recommended for most AEDs.133,134 The following drugs’ serum concentrations would only be monitored if toxicity or nonadherence was suspected:

  • Clobazam. The therapeutic range and subsequently the correlation of serum concentrations and efficacy of clobazam are not fully established. de Leon and colleagues suggest that a concentration-to-dose ratio may be more appropriate for monitoring clobazam; however, at this time therapeutic drug monitoring is not routinely used.135

  • Ethosuximide. The therapeutic range for ethosuximide is generally considered to be 40 to 100 mg/L.136 Eighty percent of patients achieve partial control within that range, and 60% are seizure free. Some patients require concentrations up to 150 mg/L.73 Side effects are usually seen at concentrations >70 mg/L and include drowsiness, fatigue, ataxia, and lethargy.73 Ethosuximide does not require as much monitoring as some of the other antiepileptics, but it is important to ensure effective concentrations after initiation of therapy or a change in dosage regimen. The half-life of ethosuximide is quite long—60 hours in adults and 30 hours in children.93 Thus, it is advised to wait as long as 1 week to 12 days before obtaining ethosuximide concentrations for monitoring purposes.14,136 Although it is generally advised that trough concentrations be obtained, concentrations drawn any time during the dosing interval should be acceptable because there will be little fluctuation if ethosuximide is given in divided doses. Peak concentrations of ethosuximide administered as a capsule are attained in 3 to 7 hours.93,136 Ethosuximide is negligibly bound to serum proteins and its metabolites have insignificant activity. Although ethosuximide is administered as a racemic mixture, the enantiomers have the same pharmacokinetic properties. Thus, measurement of the summed enantiomers is acceptable.137

  • Felbamate. It displays excellent bioavailability and is metabolized to multiple inactive metabolites. There is notable interindividual variation in felbamate’s metabolism.84 The therapeutic range of felbamate is considered to be between 30 and 60 mg/L. Dose decreases of up to 50% should be considered in patients with renal dysfunction.138 Clinically, this medication is reserved to refractory treatment due to its side effect profile and increased incidence of aplastic anemia and acute liver failure.138 Monitoring felbamate concentrations does not predict toxicity. Felbamate takes 3 to 5 days to reach steady-state concentration, and serum concentrations should not be drawn before this time. Felbamate is 22% to 25% bound to albumin and has no active metabolites. Felbamate decreases the concentration of carbamazepine and increases the concentration of carbamazepine 10, 11-epoxide, phenobarbital, phenytoin, and VPA when administered with these agents; a 20% to 25% dose reduction of aforementioned agents should be considered if it is initiated concomitantly with felbamate.139145 Simultaneously, coadministration of carbamazepine, phenobarbital, and phenytoin decreases felbamate concentrations, and VPA does not have a significant effect on felbamate concentrations.138

  • Gabapentin. Although a great candidate for therapeutic drug monitoring because of wide intrapatient variability, in large part due to changes in concentration/dose ratio with age and changes in half-life related to renal impairment, it has limited clinical use.143 Therapeutic drug monitoring is most useful in certain patient populations, including in patients with renal impairment or in those for whom adherence is questionable.84,95 The therapeutic range of gabapentin is 2 to 20 mg/L; the toxic range is ≥25 mg/L. Gabapentin is mainly renally cleared; therefore, dose adjustments are necessary in renal impairment.146 Steady state is achieved within 24 to 48 hours.147,148 Gabapentin is minimally bound to protein (<3%) and is eliminated 99% unchanged (1% is excreted as the N-methyl metabolite).149 It is recommended that serum concentrations of concomitant antiepileptic therapies be monitored if given with gabapentin.150 Linear behavior is seen at doses up to 1,800 mg/day, however nonlinear behavior is reported at higher doses because of saturable intestinal absorption.

  • Lacosamide. Due to a predictable pharmacokinetics profile and no clear correlations between therapeutic concentrations and efficacy or toxicity, therapeutic drug monitoring is not routinely recommended or needed.

  • Lamotrigine. The considerable pharmacokinetic variability among patients taking lamotrigine, due in part to significant drug–drug interactions, makes it a good candidate for therapeutic drug monitoring.133,151 The therapeutic range of lamotrigine is 2.5 to 15 mg/L.26,135,152 It has been suggested that concomitant therapy with other antiepileptics may alter the response to lamotrigine or its side-effect profile.151 The half-life of lamotrigine can range from 15 to 30 hours on monotherapy.133 Thus, one should wait at least 1 week before obtaining samples after initiating or adjusting lamotrigine therapy.151 This drug exhibits linear pharmacokinetics; therefore, dose rate adjustments result in proportional changes in average serum concentrations. Because it is only 55% bound to serum proteins, measurements of unbound lamotrigine concentrations in serum are not necessary.

  • Levetiracetam. Serum concentration monitoring of levetiracetam is more important in pregnant women and in infants and children because of the higher clearance in these patients.26,153 Furthermore, levetiracetam levels have been shown to be affected by weight and medication coadministration.154 Routine monitoring of levetiracetam is not required for most patient populations due to the predictable dose response. The half-life ranges from 6 to 8 hours in adults, and a steady state should be attained within 1 week.135 Serum concentrations between 5 and 45 mcg/mL are considered to be therapeutic.155 Serum protein binding of levetiracetam is <10%, eliminating the need for measurement of unbound levetiracetam concentrations.135 Ideally, serum concentrations should be drawn in the morning as a trough concentration due to diurinal variation in concentrations.

  • Oxcarbazepine. The pharmacologic effect of oxcarbazepine is primarily related to serum concentrations of its active monohydroxy metabolite, licarbazepine. A therapeutic range of licarbazepine is 12 to 35 mg/L.156 The elimination half-life of licarbazepine is variable, ranging from 7 to 20 hours, and is prolonged in renal impairment. The serum protein binding of licarbazepine is low at 40%.

  • Pentobarbital. As a sedative hypnotic, therapeutic effects of pentobarbital are seen at 1 to 5 mg/L; toxicity occurs at concentrations >10 mg/L. Pentobarbital is 45% to 70% bound to protein and is primarily eliminated via the kidneys. Therapeutic concentrations have not been established for antiepileptic purposes.157

  • Pregabalin. Pregabalin is approved as adjunctive treatment for partial onset seizures and for the treatment of fibromyalgia or diabetic, spinal cord injury-related, and postherpetic neuralgia. It has excellent bioavailability estimated at 98% and poor protein binding with very few drug interactions.158 It is primarily eliminated via the kidneys and, therefore, requires dose adjustment in patients with kidney dysfunction. There are no known significant active metabolites.159 Pregabalin reaches a steady state concentration at 24 to 48 hours.147,148 The therapeutic range has been defined as 3 to 8 mg/L.160,161

  • Tiagabine. Tiagabine shows pronounced interpatient pharmacokinetic variability due to strong protein binding and hepatic metabolism.162 Trough concentrations between 20 and 100 mcg/L are associated with improved seizure control, but there is wide variation in response at any given total concentration.26,133,134 This could, in part, be due to variable serum binding (96% bound in serum on average). Salicylate, naproxen, and VPA have been shown to displace tiagabine from serum proteins.133,134 Tiagabine half-life ranges from 5 to 13 hours and may be even shorter in the presence of enzyme-inducing drugs.134,153 Tiagabine shows linear elimination behavior after therapeutic doses.

  • Topiramate. Topiramate concentrations are particularly influenced by interactions with other drugs, with concentrations as much as 2-fold lower when enzyme-inducing drugs are administered concurrently.163 The half-life ranges from 18 to 23 hours, and it has linear elimination behavior.133,134,151 Topiramate is <40% bound to serum proteins but shows saturable binding to red blood cells, thus suggesting that whole blood might be a preferable specimen for monitoring.134,151 Effective serum concentrations are generally reported to be between 2 and 25 mg/L.164 No active metabolites have been identified. Routine therapeutic drug monitoring is only recommended in patients with hepatic or renal impairment.162 Saliva concentrations have a strong correlation with serum and may be a viable option for monitoring chronic therapy.165

  • Zonisamide. The pharmacokinetics of zonisamide are variable among patients and also highly influenced by interactions with other drugs.133 Zonisamide is approximately 40% bound to serum albumin, and, like topiramate, shows saturable binding to red blood cells, suggesting that whole blood monitoring might be preferable.135,151 The half-life is 50 to 70 hours but may be as short as 25 hours when enzyme inducers are coadministered.135 Some reports suggest nonlinear behavior at higher doses. The serum concentration range associated with response is 10 to 38 mg/L; cognitive dysfunction is reported at concentrations >30 mg/L.26,135,151 No active metabolites have been identified.135

Antimicrobials

Aminoglycosides

Therapeutic ranges

Aminoglycosides have been used for decades to treat infections caused by multidrug-resistant microorganisms. Most commonly used IV aminoglycosides today include amikacin, gentamicin, and tobramycin.48 They are bactericidal and their efficacy is depends highly on peak concentration after an infusion.166 Optimal bactericidal activity occurs when the peak:minimum inhibitory concentration (MIC) ratio is between 8:1 and 10:1.167169 They also exhibit a postantibiotic effect (PAE) in which bacterial killing continues even after the serum concentration falls below the MIC.73 The concentration-dependent killing and PAE of aminoglycosides explain why extended-interval, or once-daily (pulse), dosing is shown to be safe and effective in many patients. Studies have shown improved peak concentrations of aminoglycosides after extended-interval dosing of aminoglycosides when compared with multiple daily dosing regimens (ie, thrice-daily dosing). Additionally, lower trough concentrations have been reported at the end of the dosing interval compared with multiple daily dosing regimens, reducing the risk of drug accumulation.170 As a result, extended-interval aminoglycosides have been associated with improvement in efficacy and decreased nephrotoxicity.171174 Nephrotoxicity and ototoxicity are the most frequently reported adverse effects of aminoglycosides. Ototoxicity is associated with a prolonged course of treatment (for >7 to 10 days) with peaks above 12 to 14 mg/L for gentamicin and tobramycin and 35 to 40 mg/L for amikacin.73 One study noted there was not a significant difference in the incidence of ototoxicity between once-daily and multiple-daily dosing aminoglycosides.170 Patients with trough concentrations above 2 to 3 mg/L (gentamicin and tobramycin) or 10 mg/L (amikacin) for >5 to 7 days are predisposed to increased risk of nephrotoxicity.73 The risk of nephrotoxicity is even further increased when aminoglycosides are given concomitantly with other nephrotoxic agents.

Therapeutic ranges for peaks and troughs are reported for the aminoglycosides and pertain only to dosing approaches that involve multiple doses during the day. For gentamicin and tobramycin, peaks between 6 and 10 mg/L and troughs between 0.5 and 2 mg/L are recommended.175 The approximately 4-fold higher MIC for amikacin explains why peaks between 20 and 30 mg/L and troughs between 1 and 8 mg/L are recommended.175 There is no therapeutic range when the extended-interval dosing method is used; doses are given to attain peaks that are approximately 8- to 10-fold the MIC, and troughs are intended to be nondetectable within 4 hours of administration of the next dose.166,175

There has been some concern over the years that aminoglycosides are overmonitored. Uncomplicated patients who have normal renal function, do not have life-threatening infections, and will be treated for <5 days may not need to have serum aminoglycoside concentrations measured.176 At the other extreme, dosage individualization using serum concentrations of aminoglycosides is necessary in patients who are expected to be on prolonged treatment courses (≥5 days) or in whom unusual pharmacokinetic parameters are expected.173180

Sample timing

For extended-interval dosing patients with normal renal function, a steady state is never reached because each dose is washed out prior to the next dose. The method developed by Nicolau et al (the Hartford nomogram) requires that a single blood sample be obtained between 6 and 14 hours after the end of the first infusion.167,181 This sample is referred to as a random sample, but the time of the collection must be documented. The concentration is used with a nomogram to determine if a different dosing interval should be used.48,167 Concentrations that are too high according to the Hartford nomogram indicate that the drug is not being cleared as well as originally predicted, suggesting the need for a longer dosing interval. For traditional dosing, it is important to wait until a steady state is reached before obtaining serum concentrations. The half-lives of the aminoglycosides are 1.5 to 3 hours for adults with normal renal function but as long as 72 hours in patients with severe renal impairment.73 A conservative rule of thumb is that steady state is reached after the third or fourth dose.48 Some patients may have blood samples drawn immediately after the first dose (“off the load”) to determine their pharmacokinetic parameters for purposes of dosage regimen individualization. These would most likely be patients who are anticipated to have unpredictable or changing pharmacokinetic parameters, such as those in a critical care unit, and who require immediate effective treatment because of life-threatening infections.

Two blood samples are sufficient for purposes of individualizing traditional aminoglycoside dosing therapy and provide reasonable estimates of aminoglycoside pharmacokinetic parameters.182 It is crucial that the times of the sample collections be accurately recorded.48,166 The two samples should be spaced sufficiently apart from each other so that an accurate determination of the log-linear slope can be made to determine the elimination rate constant. The first sample, sometimes referred to as the measured peak, should be drawn no earlier than 1 hour after the end of a 30-minute infusion.182185 However, it is usually drawn within 30 minutes prior to the start of infusion of the next dose (assumed to be the trough).48,164,176 Once the elimination rate constant has been calculated using these two concentrations, the true peak and true trough can be calculated and their values compared with desired target peaks and troughs.

Use of concentrations for dosage adjustment

Various extended-interval dosing methods are used to take advantage of the concentration-related killing and PAE of aminoglycosides.176 The original Hartford method involves giving a milligram-per-kilogram dose that is administered to attain a peak concentration that is approximately 10 times the MIC. Then a sample is obtained between 6 and 14 hours after the end of the infusion and compared with a nomogram, which indicates the appropriate maintenance dosing interval—usually 24, 36, or 48 hours.167

Serum concentrations of aminoglycosides obtained during traditional dosing are used to determine an individual patient’s pharmacokinetic parameters as well as the true peak and true trough to compare these to desired target concentrations. Equations that account for time of drug infusion are used to determine an appropriate dosing interval and dose.185 Other dosage adjustment methods include nomograms and population pharmacokinetic (Bayesian) methods.177,185

Protein binding, active metabolites, and other considerations

Aminoglycosides are <10% bound to serum proteins, and unbound concentrations will always reflect total concentrations in the serum.175 The metabolites of the aminoglycosides are inactive.

Vancomycin

Therapeutic range and clinical considerations

Vancomycin is a glycopeptide antibiotic that is used intravenously to treat gram-positive organisms, including those resistant to other antibiotics (ie, methicillin-resistant Staphylococcus aureus [MRSA]).48,73 The emergence of vancomycin-resistant enterococci, vancomycin-resistant S aureus, vancomycin-intermediate S aureus (VISA), and heteroresistant VISA has led to the need to optimize and restrict vancomycin use. Major toxicities associated with vancomycin are nephrotoxicity and ototoxicity. Another adverse effect known as red man syndrome (intense flushing, tachycardia, and hypotension) is a histamine-related reaction associated with rapid infusion.73,186

Although some institutions may monitor both peaks and troughs of vancomycin, this practice has been questioned because of a lack of standardization in associating timing of sample draw and peak concentration. In contrast to aminoglycosides, the most important pharmacodynamic parameter of vancomycin when used against S aureus isolates is 24-hour AUC to MIC, with a target of 400 to 600 mg × h/L. Historically, due to ease of use and practicality, trough concentrations served as surrogates for the AUC/MIC target, with troughs of 15 to 20 mg/L recommended for infections caused by S aureus isolates with MICs ≤1.187 Although this traditional trough-based monitoring recommendation has been widely practiced in recent years, benefits for maintaining higher troughs are not well supported, and more recent evidence has emerged noting that trough concentrations may not correlate well with AUC values—risking either overexposure (and increased risk of associated toxicities) or underexposure (and increased risk of emergence of antimicrobial resistance). Therefore, new guidelines recommend that in patients with suspected or confirmed MRSA infections that individualized AUC/MIC ratio of 400 to 600 mg × h/L is targeted using AUC-guided dosing and monitoring, which can be accomplished by either two-point kinetics or through the use of Bayesian software programs (preferred method). There remains a gap in available evidence on the most appropriate AUC/MIC ratio target for non-MRSA infections, which the recent guidelines have not addressed. Therefore, the use of the aforementioned targets for non-MRSA infections should be extrapolated with caution if opted to be used in these scenarios.187

Sample timing

The half-life of vancomycin is 7 to 9 hours in adults with normal renal function and 120 to 140 hours in patients with renal failure. A shorter half-life of 3 to 4 hours has been noted in certain patient populations (ie, obesity, burn victims).73,188 For AUC-guided dosing and monitoring, either a two-point kinetic or Bayesian software approach can be followed. With two-point kinetics, it is recommended that once steady state is achieved, one concentration be obtained at the postdistribution phase (peak concentration at 1 to 2 hours after infusion) and a second concentration at the end of the dosing interval (trough). If Bayesian software is used, one or two vancomycin concentrations (with one of the concentrations being a trough) should be obtained to help estimate the AUC although a two-concentration approach is preferred. The latter approach does not require steady-state concentration to be reached first, thereby allowing for early AUC target assessment. Of note, a trough concentration may be appropriate to estimate the AUC using the Bayesian approach in certain patient populations.187 For traditional (historical) concentration monitoring, samples should be obtained as troughs within 30 minutes to 1 hour of the start of the next infusion.

Use of concentrations for dosage adjustment

Because of the increased risk of nephrotoxicity in patients with serious MRSA infections, a trough-only based monitoring approach, targeting troughs of 15 to 20 mg/L, is no longer recommended and an AUC-monitoring approach is advocated instead. Of note, the aforementioned recommendation is only for serious MRSA infections. Whether a traditional trough-only monitoring versus an AUC-guided dosing and monitoring approach is best for other infections has not been determined. Besides serious MRSA infections, monitoring is recommended for patients at high risk for nephrotoxicity, patients with unstable renal function, and patients receiving extended courses of vancomycin therapy (ie, >3 days). Vancomycin elimination is linear, and an increase in the dose (without a change in the dosing interval) can be expected to provide a proportional change in the trough serum concentration. It must be cautioned that vancomycin has a pronounced distribution phase, making the standardization of any peak sample to be especially important. More sophisticated prediction methods for dosing adjustments must be used if the dosing interval is adjusted with or without a change in dose.

Many methods have been proposed for vancomycin dosage regimen adjustments.73,78,188,189 A relatively simple method, proposed by Ambrose and Winter, permits the use of a single trough concentration (drawn within 1 hour of the start of the next infusion) along with an assumption of the population distribution volume to predict the necessary pharmacokinetic parameters needed for individualization.186 Once those parameters are determined, equations that account for drug infusion can be used to target desired peak and trough vancomycin concentrations. For AUC-guided dosing, monitoring of AUC exposure is recommended in obesity and patients with changing renal function. More frequent monitoring may be needed in patients exhibiting hemodynamic instability.

Protein binding, active metabolites, and other considerations

Vancomycin is 30% to 55% bound to serum proteins in adults with normal renal function. The binding is lower (19%) in patients with ESRD.189 With binding this low, total concentrations of vancomycin provide reliable reflection of the unbound concentrations in serum. Vancomycin metabolites are inactive and thus do not contribute to antibacterial effect or toxicity.

β-Lactams

Therapeutic range and clinical considerations

The β-lactam antibiotics demonstrate time-dependent bactericidal killing with efficacy related to the percentage of the dosing interval that free drug concentration remains above the MIC (fT>MIC). Studies have shown that the killing potential of β-lactams is maximized at concentrations that are three to four times the MIC, with higher concentrations providing little, if any, additional benefit.190 Therefore, it is important to optimize exposure of β-lactams by increasing dosing frequency or infusion duration. Generally, fT>MIC of 40%, 50%, and 50% to 70% is required for the bactericidal killing potential of carbapenems, penicillins, and cephalosporins, respectively.191 As demonstrated by an increase in Vd and changes in antibiotic clearance (either increased or decreased), β-lactam antibiotic pharmacokinetics may be altered in critically ill patients. Additionally, obesity can similarly alter antibiotic pharmacokinetic parameters. As a result, standard doses of antibiotics may be suboptimal, leading to inadequate concentrations and even toxicities in some situations.192 Roberts and colleagues noted that one-fifth of critically ill patients did not achieve a pharmacokinetic/pharmacodynamic target of 50% fT>MIC when standard antibiotic doses were used.193 Historically, therapeutic drug monitoring of β-lactam was not undertaken because these agents lack a narrow therapeutic window and toxicity that would necessitate monitoring. As the incidence of multidrug-resistant microorganisms continues to increase, dosing optimization of currently available antibiotics is more important than ever and provides a potential role for β-lactam therapeutic drug monitoring, especially in the critically ill patient population and other patients with known pharmacokinetic variability.190,194

Antifungal Agents

Flucytosine (5-FC)

Therapeutic range and clinical considerations

Flucytosine is a synthetic antifungal agent used in combination with amphotericin B for treatment of select systemic fungal infections (ie, cryptococcal meningitis).195 In vivo and animal studies have noted that time above MIC is the most important pharmacodynamic parameter related to outcome with flucytosine therapy.196 Flucytosine has significant interpatient pharmacokinetic variability. Although no exact target range for serum concentrations of flucytosine has been established, most clinicians agree that peak serum concentrations (2 hours postdose) of flucytosine should be kept below 100 mg/L to avoid dose-related hepatotoxicity, bone marrow suppression, and GI disturbances.166,197,198 Additionally, concentrations should not fall below a trough concentration of <20 to 40 mg/L to avoid the development of resistance.166,197199 Hepatotoxicity and bone marrow suppression are usually reversible with discontinuation. Indications for monitoring flucytosine include avoidance of toxicity—particularly in patients with impaired renal function or those receiving concomitant amphotericin B—and avoidance of development of resistance due to sustained low concentrations.167,195197

Sample timing

Flucytosine is minimally protein bound (2% to 4%) and undergoes minimal hepatic metabolism. It is primarily (90%) excreted in the urine as unchanged drug, with an elimination half-life of 4 to 5 hours in patients with normal renal function and upwards of 250 hours in ESRD.196,197,200 Maximum serum concentration is reached within 1 to 2 hours after an oral dose at steady state in patients with normal renal function.199 Therefore, a 2-hour postdose concentration of flucytosine should be obtained after three to five doses have been administered, noting that steady state may not be reached for approximately 10 days in patients with renal failure.195,196 Trough concentrations, if indicated, should be drawn within 30 minutes of the next dose.

Use of concentrations for dosage adjustment

Because there are no reports of nonlinear elimination behavior, a given increase in dose should produce a proportional increase in serum flucytosine concentration. Therapeutic drug monitoring is considered standard of care for the use of flucytosine and it is recommended that serum concentrations be obtained at 72 hours after therapy initiation, when there are concerns with adherence, or if there are signs of drug-related toxicities.199

Azole Antifungals

Therapeutic ranges and clinical considerations

The incidence of fungal infections has been on the rise as the number of patients at risk has increased (eg, patients receiving immunosuppressive therapy). Azole antifungal agents are used to treat several different fungal infections, including invasive candidiasis, aspergillosis, and mucormycosis. The primary reason for monitoring azole antifungal drugs is to ensure efficacy and safety as they have demonstrated wide interpatient pharmacokinetic variability. Suboptimal azole antifungal concentrations have been associated with treatment failure and fungal breakthrough, whereas high concentrations have been related to toxicities (eg, hepatotoxicity).

Itraconazole

Itraconazole concentrations are known to be relatively low in patients with AIDS or acute leukemia, most likely due to malabsorption and concurrent administration of enzyme-inducing drugs.201 Additionally, absorption of the oral capsule formulation greatly depends on the gastric pH; itraconazole capsule formulation demonstrates improved absorption in an acidic environment. This necessitates the administration of the oral capsule with a full meal or acidic beverage (eg, cola). Conversely, the oral liquid solution’s absorption is improved when not taken with food.196 The newest formulation of itraconazole uses SUper-Bio-Available technology, which enhances the bioavailability of poorly soluble drugs, thereby increasing the relative bioavailability of itraconazole to 173% and involves less interpatient variability in plasma concentrations.202,203 Itraconazole displays nonlinear pharmacokinetics. It undergoes significant first-pass metabolism into several metabolites—most importantly, hydroxy-itraconazole—with levels approximately double those of itraconazole. Although some isolates of yeasts and mold are more susceptible to hydroxy-itraconazole or itraconazole, they have comparable in vitro antifungal activity.202 It has been noted that mortality and breakthrough infections are more common with itraconazole trough concentrations <0.5 mg/L and toxicity with concentrations >3 mg/L. Efficacy has been associated with itraconazole concentrations of 0.5 to 1 mg/L. Itraconazole accumulates slowly and reaches concentrations of 0.5 to 1 mg/L after 1 to 2 weeks. Due to slow accumulation, a loading dose is recommended to assist with reaching therapeutic concentrations sooner, namely in serious fungal infections. Additionally, itraconazole inhibits CYP3A4, leading to a number of significant drug interactions.204 Due to interpatient and absorption variability based on the administered formulation, some consider the serum concentration monitoring of itraconazole to be essential in patients with life-threatening fungal infections.205 Measuring itraconazole concentrations is recommended to ensure adequate absorption, monitor the need for dosage changes (eg, when interacting medications are added or discontinued), and assess adherence to therapy. Because of a long elimination half-life (34 to 42 hours after multiple doses), the concentration of itraconazole can be drawn at any time during a dosing interval once steady state is reached (at approximately 2 weeks).206,207

Voriconazole

Voriconazole is a first-line treatment option for invasive aspergillosis and other invasive fungal infections. It exhibits nonlinear pharmacokinetics (Michaelis-Menten) related to saturable clearance mechanisms. This leads to greatly variable and unpredictable changes in drug exposure secondary to dosage adjustments and interpatient pharmacokinetic variability.196,202 The most important pharmacodynamic parameter is AUC/MIC with a value of >25 associated with clinical efficacy in infections due to Candida and Aspergillus spp. Voriconazole has excellent bioavailability; however, it is metabolized by several significant CYP450 enzymes (ie, CYP2C9, CYP3A4, and CYP2C19). These enzymes may have significant interpatient variability due to enzyme polymorphism and, therefore, lead to varying voriconazole concentrations.196 Suboptimal voriconazole concentrations have been associated with suboptimal response and treatment failure. Additionally, elevated voriconazole concentrations have been correlated with toxicities, which include hepatotoxicity, visual disturbances, and hallucinations. Based on available data, voriconazole concentrations between 1 mg/L and 4 to 6 mg/L are recommended to increase efficacy and decrease risk of toxicity. A trough concentration (eg, end of 12-hour dosing interval) should be drawn within the first week of therapy initiation or dosage adjustment.196,204,208,209

Posaconazole

Posaconazole is indicated for the treatment of several invasive fungal infections, including mucormycosis. Posaconazole is available as an oral suspension, delayed-release tablet, and IV solution.210 The oral formulations (oral suspension and delayed-release tablet) are not interchangeable because of noted pharmacokinetic differences. The oral formulations are influenced by food intake. Additionally, the oral suspension is influenced by gastric pH. It is recommended that the oral suspension be given with a high-fat meal to enhance bioavailability (by 2.6 to 4 times).204,208 Similar to previously mentioned azole antifungals, posaconazole demonstrates large interpatient variability in its pharmacokinetic parameters. An exposure–toxicity relationship is still unknown for posaconazole.196,202,208,209 Because of the prolonged half-life of posaconazole (26 to 35 hours), steady state is not reached until the end of first week of therapy, and serum concentrations can be measured at any time during the interval at that point.204,208 Greater clinical response to posaconazole has been related to higher drug concentration exposure. Although a recommended trough concentration has not been defined, some have suggested a trough of >0.7 mg/L or >0.9 mcg/mL for prophylaxis, and a trough of >1 mg/L for primary therapy and >1.25 mg/L for salvage therapy or >1.8 mg/L in treatment of invasive fungal infections.202,204

Fluconazole

Therapeutic drug monitoring of fluconazole is not required due to predictable concentrations based on currently available data. Additionally, it is less affected by drug–drug interactions. Of note, an AUC/MIC ratio >25 to 50 is related to improved clinical outcomes.196,202,205

Isavuconazole

Although most patients achieve concentrations >1 mg/L with standard recommended doses, therapeutic drug monitoring of isavuconazole is not recommended at this time because of lack of efficacy or toxicity thresholds in the treatment of invasive aspergillosis or mucormycosis.202,211

Antimycobacterials

Drugs that are FDA-approved and considered first line as part of an initial four-drug regimen are isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Of these, isoniazid and rifampin are the most important based on their relatively high potency and favorable side-effect profiles. Second-line agents that are more toxic must be used if drug resistance emerges and include ethionamide, cycloserine, capreomycin, para-aminosalicylic acid, and dapsone.212

The practice of therapeutic drug monitoring for antituberculosis drugs varies among experts. It is used to provide insight into drug dosing and dose adjustments. Scenarios in which therapeutic drug monitoring may be beneficial include poor response despite therapy adherence and drug-susceptible regimens, severe GI abnormalities in which absorption may be questioned, and drug–drug interactions.213 Low concentrations of isoniazid and rifampin have been associated with slow disease response, relapse, and emergence of drug resistance.214 In fact, poor treatment outcomes have been related to low tuberculosis (TB) drug exposure, noting an estimated 9-fold increase in treatment failure.215 As a result, it is essential that adequate concentrations of these antimycobacterial drugs be present in serum for effective treatment and avoidance of negative consequences. This does not always occur, even in patients in whom adherence has been documented.212 Lower-than-expected concentrations of antimycobacterial drugs have been reported in patients with diabetes and in individuals with HIV infections, which in some cases was associated with malabsorption.216218 There is also considerable potential for drug–drug interactions among the antimycobacterial drugs, given the effects of rifampin, isoniazid, and the fluoroquinolones in either inducing or inhibiting cytochrome P450 isozymes.219 Drugs used to treat patients with HIV may also contribute to additional drug–drug interaction concerns.

A study in patients without HIV who are infected with TB who were not responding to treatment as expected showed that 29% to 68% of them had serum antimycobacterial drug concentrations below target ranges.220 In another study, a small percentage of nonresponding patients all showed suboptimal concentrations of rifampin.221 After dosage adjustments were made, all patients responded to treatment. The authors recommended that low serum rifampin concentrations be suspected in patients who do not respond after 3 months of supervised drug administration or earlier in patients with HIV infection, malnutrition, known GI or malabsorptive disease, or hepatic or renal disease.

Most TB drugs display AUC/MIC as the most important pharmacodynamic parameter; however, the relationship between dose or serum concentrations and toxicity is not well established (exceptions include pyrazinamide, ethambutol, and cycloserine). Several TB drugs display significant interpatient variability, necessitating therapeutic drug monitoring of these agents to avoid potential associated treatment failure, relapse, and toxicity.222

Specialized laboratories have been developed that offer sensitive and specific assays for serum concentrations for the most commonly used antimycobacterial drugs.212 As more specific information about the efficacy of therapeutic drug monitoring of these drugs becomes available, more laboratories and services of this type will likely be available.223

Antiretrovirals

Therapeutic Ranges and Clinical Considerations

Overall, there is a paucity of published literature correlating clinical outcomes in adults infected with HIV and drug concentrations. Significant interpatient variability exists in regard to pharmacokinetics of antiretroviral drugs. Therapeutic concentration ranges, therefore, have not been established for most antiretrovirals.224,225 Furthermore, antiretroviral regimens are administered as fixed doses; therefore, dose adjustments, as seen with other drug classes requiring therapeutic drug monitoring, may not be feasible or useful.226 Although routine monitoring of antiretroviral agents is not recommended, there are some scenarios in which therapeutic drug monitoring should be considered. These situations include instances in which significant drug–drug or drug–food interactions may lead to reduced efficacy or toxicities; physiologic and anatomic changes (eg, GI) that may impair drug absorption or metabolism; pregnancy in which women do not achieve virologic clearance; and cases in which treatment-experienced patients have developed virologic failure.227 There is some evidence that favors limited serum concentration monitoring of drugs used in the treatment of HIV-1 infection, in particular, the PIs and the non–nucleoside reverse-transcriptase inhibitors (NNRTIs).228,229 These drugs, particularly the PIs, show marked interpatient variability in their pharmacokinetics, and their serum concentrations correlate with virologic response and failure.230,231 A substudy of the randomized, prospective clinical trial AIDS Therapy Evaluation in the Netherlands showed that patients who underwent serum drug concentration monitoring for antiretroviral drugs had a significantly higher likelihood of virological response as compared with those who did not undergo monitoring.230 Of note, the study was conducted in antiretroviral-naive patients. The same results have not been shown in subsets of antiretroviral–experienced patient populations. Assays for drug concentrations are available commercially for some antiretrovirals although there is a lag time in results being reported.226,227

Minimum concentration (Cmin) is the proposed target concentration parameter.229 Minimum effective concentrations have been determined for the most common PIs based on in vitro determinations of drug concentrations (corrected for serum binding) required for 50% or 90% inhibition of replication in a patient’s virus isolate (IC50 or IC90). Attention has turned more recently, however, to the use of a new parameter that may be a better predictor of response. The inhibitory quotient (IQ) is the ratio of the trough plasma concentration to the IC50 or IC90.230 A high IQ indicates more drug is present in the patient than is needed for a virologic response, whereas a low IQ indicates inadequate drug concentrations or a resistant virus. Recent studies show the virologic response may be better related to IQ than to trough concentrations alone.230 Future studies may focus on the definition of therapeutic ranges of IQ rather than minimum concentrations.

Some clinicians advocate the monitoring of PI and NNRTIs in all patients upon the initiation of therapy to ensure adequate concentrations; others reserve the use for selected situations, including patients with renal or liver disease, pregnant patients, children, patients at risk for drug interactions, and patients with suspected toxicity.230,232

Sample Timing

Half-lives of NNRTIs average 25 to 50 hours, and steady state is reached after a week in most patients.233 However, a steady state is reached within 2 days for the PIs, which have half-lives ranging from 2 to 12 hours.233 Predose samples are recommended as the minimum effective concentrations, and IQs are based on the lowest drug concentration during the dosing interval. There may be logistical problems with this timing, however, in cases in which the drug is administered once daily in the evening. Some drugs, such as nelfinavir, exhibit a lag in their absorption, such that the lowest concentration actually occurs about an hour after administration of the next dose.

Use of Concentrations for Dosage Adjustment

Dosage adjustments of antiretroviral drugs, for the most part, should result in proportional changes in the trough serum drug concentration, provided the dosing interval is not altered. As mentioned previously, antiretroviral doses are fixed; therefore, there is no guidance on dose adjustment based on available drug concentrations. Reports showing serum drug concentrations to be unpredictable after dosage adjustments in some patients suggest that nonadherence with antiretroviral regimens is a major concern.231 Serum concentrations of amprenavir, lopinavir, nelfinavir, and saquinavir may be difficult to maintain above their minimum effective concentrations because of rapid clearances and large first-pass effects. Rather than increasing their dose, ritonavir, a potent inhibitor of CYP3A4-mediated metabolism in the gut wall and liver, may be coadministered as a pharmacoenhancer. This results in decreased GI enzyme metabolism of the PI, higher trough concentrations, and, in most cases, prolonged elimination half-lives.234

Protein Binding, Active Metabolites, and Other Considerations

The serum protein binding of nevirapine and indinavir is 50% to 60%, whereas the protein binding of the other antiretrovirals is >90%.242,245 Albumin and AAG are the primary binding proteins for these drugs in serum.232 As would be expected, there is considerable variability in the unbound fraction of these drugs in serum. In addition, AAG concentrations are elevated in patients with HIV-1 infection and can return to normal with treatment. Thus, the same total concentration of the drug would be expected to reflect a lower concentration of response early in treatment as compared with later. Clearly, total concentrations of the PIs and NNRTIs should be cautiously interpreted if unusual serum binding is anticipated, but no clear guidelines are yet available. Only nelfinavir has a metabolite that is known to be active.230 Although studies indicate the measurement of the metabolite is probably not crucial, there is likely to be considerable variability among and within patients in the presence of this metabolite.

Cardiac Drugs

Digoxin

Therapeutic range and clinical considerations

Since the advent of therapeutic drug monitoring, there has been a dramatic reduction in digoxin toxicity.236 Routine monitoring is not necessary unless digoxin toxicity is expected, the patient has declining renal function, there is a suspected change in pharmacokinetics due to changing condition, or there is an initiation of concomitant interacting medications.237 Additionally, patients with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, and hypercalcemia), hypothyroidism, myocardial ischemia, and acidotic states are at higher risk of toxicity. Patients with hyperthyroidism are believed to be more resistant to digoxin.30

Digoxin’s inotropic effect is the basis for its use for the management of heart failure, while its chronotropic effects are the basis for the management of atrial arrhythmias, such as atrial fibrillation and atrial flutter. The commonly reported therapeutic range is 0.5 to 2 mcg/L in adults and 1 to 2.6 mcg/L in neonates.76,235,237 The lower end of the range (0.5 to 1 mcg/L) is generally used for treatment of heart failure.238 Results of the Digitalis Investigation Group trial found in a post hoc analysis that concentrations of 0.5 to 0.8 mcg/L in men with heart failure (left ventricular ejection fraction <46%) reduced hospitalizations.239 Dosing strategies for patients with heart failure have been established based on kidney function, age >70 years, ideal body weight, and height.240242 Higher serum digoxin concentrations may be required for treatment of atrial arrhythmias (0.8 to 1.5 mcg/L), with concentrations up to 2 mcg/L previously showing benefit in some patients.73 More recent studies have shown an increased mortality in patients treated with digoxin with a serum concentration of >1.2 mcg/L; however, as noted previously, routine monitoring is not indicated.

Fifty percent of patients with serum digoxin concentrations >2 mcg/L show some form of digoxin toxicity; toxicity may be experienced at lower concentrations, and management should be based on symptoms.73,243 Symptoms of toxicity include muscle weakness; GI reports (anorexia, nausea, vomiting, abdominal pain, and constipation); CNS effects (headache, insomnia, confusion, vertigo, and changes in color vision); and serious cardiovascular effects (second- or third-degree atrioventricular bradycardia, premature ventricular contractions, and ventricular tachycardia) (Table 5-4).73,237

TABLE 5-4.
Digoxin Toxicities245

Cardiac effects

  • Arrhythmias

  • Sinus bradycardia

CNS/GI effects

  • Anorexia, nausea, vomiting, abdominal pain

  • Visual disturbances: halos, photophobia, color perception dysfunction (red-green or yellow green), scotomata

  • Fatigue, weakness, dizziness, headache, confusion, delirium, psychosis

Sample timing

The average digoxin half-life in adults with normal renal function is approximately 2 days; at least 7 days are recommended to attain a steady state.237 In the case of treatment of digoxin overdose with digoxin-immune Fab fragments (a fragment of an antibody that is very specific for digoxin), blood samples for serum digoxin measurements should not be obtained sooner than 10 days after administration of the fragments.235,237

Samples drawn during the absorption and distribution phases after administration of digoxin cannot be appropriately interpreted by comparison with the usual therapeutic range. Digoxin concentrations in blood do not reflect the more important concentrations in myocardial tissue until at least 6 hours after the dose (some say at least 12 hours).237,245,246 Therefore, blood samples should be drawn anytime between 6 hours after the dose and right before the next dose (Figure 5-5). Ideally, blood samples would be drawn as a trough concentration just prior to the next dose.

FIGURE 5-5.
FIGURE 5-5.
Simulated plot showing concentrations of digoxin in serum (microgram/liter) and concentrations in myocardial tissue (units not provided) after a dose of digoxin at steady state. Tissue concentrations do not parallel concentrations in serum until at least 6 hours after the dose.

Inappropriate timing of samples for digoxin is problematic. One study revealed that 55% of the samples submitted to the laboratory for digoxin analysis lacked clinical value because of inappropriate timing.247 In another study, standardization of digoxin administration and blood sampling times resulted in a dramatic reduction in inappropriately timed samples (ie, timed at 5:00 p.m. for digoxin administration and timed at 7:00 a.m. for blood sampling).248 Another recommendation is that the laboratory immediately contact the clinician if digoxin concentrations are >3.5 mcg/L.237 If it is confirmed that the sample was drawn too early after the dose, another sample should be requested. If monitoring is considered at the initiation of therapy, serum concentrations should be drawn within 12 to 24 hours of the loading dose; if no loading dose is administered, clinicians should wait 3 to 5 days after therapy initiation to evaluate concentrations.249 It should be noted that concentrations drawn after administering a loading dose can assist in ensuring adequate concentrations are achieved; however, they cannot guide maintenance dosing.

Use of concentrations for dose adjustment

Because of the linear elimination behavior of digoxin, a given increase in the daily digoxin dose produces a proportional increase in the serum concentration at that time during the dosing interval. To determine steady-state concentrations after dose adjustments, obtain a serum concentration 5 to 7 days after any dose change, and periodically thereafter, particularly in instances of potential change in pharmacokinetics, as detailed previously. In patients with ESRD, steady state may not be obtained for 15 to 20 days.249

Protein binding, active metabolites, and other considerations

Digoxin is only 20% to 30% bound to serum proteins.29 Therefore, total concentrations in serum will reflect the pharmacologically active unbound concentration. The biologic activity of digoxin metabolites is modest compared with the parent drug, and variable presence of metabolites should not affect the interpretation of a digoxin serum concentration.

Other Cardiac Drugs

Amiodarone

Amiodarone is used for the treatment of life-threatening recurrent ventricular arrhythmias that do not respond to adequate doses of other antiarrhythmics and is commonly used in the management of recurrent atrial fibrillation/flutter. The primary metabolite, desethylamiodarone (DEA), has similar electrophysiologic properties as amiodarone and accumulates at concentrations similar to or higher than the parent drug, especially in patients with renal failure.235 Concentrations of amiodarone and desethylamiodarone demonstrate linear pharmacokinetics with increasing doses of amiodarone.250 The concentration versus effect relationship for amiodarone is poorly defined; some say that serum concentrations between 0.5 and 2.5 mg/L are associated with effectiveness with minimal toxicity.235 The occurrence of toxicity has been reported at plasma concentrations >2.5 mg/L.251253 Laboratories that measure serum amiodarone concentrations report only the parent drug, despite high concentrations of the active metabolite. In general, therapeutic drug monitoring of amiodarone is of limited benefit because activity of the drug is mostly associated with concentrations in the tissue.246 Serum concentrations might be most useful in cases of suspected nonadherence or toxicity.

Lidocaine

Lidocaine is a type 1B antiarrhythmic used as second-line therapy for the acute treatment for ventricular tachycardia and fibrillation with modern use primarily as off-label for pain. The therapeutic range is generally considered to be 1.5 to 5 mg/L with concentrations >6 mg/L considered to be toxic.73,238,255 Minor side effects—drowsiness, dizziness, euphoria, and paresthesias—may be observed at serum concentrations >3 mg/L. More serious side effects observed at concentrations >6 mg/L include muscle twitching, confusion, agitation, and psychoses, whereas cardiovascular depression, atrioventricular block, hypotension, seizures, and coma may be observed at concentrations >8 mg/L.73,237,255 Lidocaine concentrations are not monitored as commonly with short-term use because its effect (abolishment of the electrocardiogram-monitored arrhythmia or pain relief) is easy to directly observe and is generally not indicated when used for pain management given administration is generally limited to single doses. Electrocardiogram monitoring may be indicated and is typically part of institutional protocols. Indications for drug concentration monitoring should be restricted to situations in which the expected response is not evident or when decreased hepatic clearance is suspected or anticipated: liver disease, heart failure, advanced age, severe trauma, and concurrent drugs such as β-adrenergic blockers, fluvoxamine, or cimetidine.235,237,254 Additionally, serum concentrations should be monitored in the case of extended use, although infusion duration beyond 6 hours is not recommended.256 The half-life of lidocaine ranges from 1.5 hours to as long as 5 hours in patients with liver disease; thus, steady state may not be attained for 18 to 24 hours.73,255 Because lidocaine is administered as a continuous infusion, there are no fluctuations in concentrations, and blood lidocaine serum concentrations can be drawn anytime once steady state is reached. Adjustments of lidocaine infusion rate should result in a proportional increase in lidocaine serum concentration. The unbound percentage of lidocaine is normally 30% but can range from 10% to 40% due to variations in AAG concentrations.73,237 The combination of higher total concentrations of lidocaine during prolonged infusions and a lower unbound fraction mean that unbound lidocaine concentrations during prolonged infusions are probably therapeutic.257 The monoethylglycinexylidide metabolite of lidocaine has 80% to 90% of the antiarrhythmic potency of lidocaine, and its concentration accumulates in renal failure.73,254

Mexiletine

Several early studies with mexiletine have established a linear association with serum concentrations and toxicity. Currently, the clinically used therapeutic range is 0.8 to 2 mcg/mL; however, it should be noted the establishment of this therapeutic range was in the prophylaxis of ventricular tachycardia after myocardial infarction, not in the treatment of ventricular tachycardia, which is the most common use.258260 Despite the potential benefit of therapeutic drug monitoring for mexiletine in some patient populations, specifically those with hepatic dysfunction, serum concentrations are not widely used and when they are used, they do not often result in a change to therapy.

Procainamide

Although the oral formulation is no longer available in the United States, the IV form of procainamide is used for patients with atrial fibrillation or flutter who require cardioversion.261,262 The therapeutic range of procainamide is complicated by the presence of an active metabolite, NAPA, which has different electrophysiologic properties than the parent drug. Procainamide is a type 1A antiarrhythmic, whereas NAPA is a type III antiarrhythmic.73,235,237 The enzyme that acetylates procainamide is bimodally distributed, such that patients are either slow or fast acetylators. In addition, NAPA depends more on the kidneys for elimination than procainamide.247,263 Most patients respond when serum procainamide concentrations are between 4 and 8 mg/L; some patients receive additional benefit with concentrations up to 12 mg/L.261 There have been reports of patients requiring concentrations between 15 and 20 mg/L without adverse effects.261 Serum concentrations of NAPA associated with efficacy are reported to be as low as 5 mg/L and as high as 30 mg/L. Most clinicians consider toxic NAPA concentrations to be >30 to 40 mg/L.237 Some clinicians feel that NAPA does not need to be monitored except in patients with renal impairment.261 Most laboratories automatically measure both procainamide and NAPA concentrations in the same sample. The practice of summing the two concentrations and comparing it to a therapeutic range for summed procainamide and NAPA (often reported as 10 to 30 mg/L) is to be discouraged.73,237,261 To do this validly, the molar units of the two chemicals would need to be used.238 The best practice is to independently compare each chemical to its own reference range.73,237,265 Side effects to procainamide and NAPA are similar. Anorexia, nausea, vomiting, diarrhea, weakness, and hypotension may be seen with procainamide concentrations >8 mg/L, although concentrations >12 mg/L may be associated with more serious adverse effects: heart block, ventricular conduction disturbances, new ventricular arrhythmias, and even cardiac arrest.73 Indications for procainamide and NAPA serum concentration monitoring include recurrence of arrhythmias that were previously controlled, suspected toxicity or overdose, anticipated pharmacokinetic alterations caused by drug–drug interactions (including amiodarone, cimetidine, ethanol, ofloxacin, quinidine, ranitidine, and trimethoprim), and disease state changes (renal failure or heart failure, in particular).73,237,261,263 The half-life of procainamide in adults without renal impairment or heart failure ranges from 2.5 hours (fast acetylator) to 5 hours (slow acetylator).73,237 The half-life of NAPA is longer, averaging 6 hours in patients with normal renal function and 30 hours or longer in patients with renal impairment.73,261 Thus, a steady state of both chemicals is not observed until at least 18 hours in patients with good renal function or as long as 4 days in renal impairment. The lower clearance of procainamide at higher doses has been attributed to nonlinear hepatic clearance.264 The clinician should be aware that increases in infusion rate may produce somewhat greater-than-proportional increases in serum procainamide concentration in some patients, particularly those with serum concentrations at the upper end of the therapeutic range. Procainamide is only 10% to 20% bound to serum proteins.235,238 Thus, total procainamide and NAPA concentrations always reflect the pharmacologically active unbound concentrations of these drugs.

Quinidine

The therapeutic range of quinidine for treatment of severe malaria due to Plasmodium falciparum is reported as 3 to 6 mg/L.265 When used in combination with verapamil for prevention of atrial fibrillation, the therapeutic range of quinidine is reported to be 2 to 6 mg/L, although use of quinidine is not strongly recommended due to a 3-fold increased risk of cardiac death when compared with other antiarrhythmic agents.265268 Common side effects are anorexia, nausea, and diarrhea; more serious side effects include cinchonism, hypotension, and ventricular arrhythmias.73,237 Torsades de pointes is more likely to occur at lower concentrations of the therapeutic range, thus complicating the interpretation of quinidine concentrations.235 Indications for monitoring of quinidine concentrations include therapeutic confirmation, suspected toxicity, recurrence of arrhythmias, drug–drug interactions, suspected nonadherence, and changes in formulation.73,237,268 The half-life of quinidine is reported to range from 4 to 8 hours in adults and up to 10 hours in patients with liver disease. Steady state should be attained within 2 or 3 days in patients with normal hepatic function, and most clinicians agree that samples should be drawn as a trough within 1 hour of the next dose.73,235,237,268 Quinidine is a weak base that is normally between 70% and 80% bound to albumin and AAG.237 The unbound fraction of quinidine was shown to be decreased in patients with atrial fibrillation or atrial flutter, and the unbound quinidine concentration was shown to correlate better with electrocardiogram interval changes than total quinidine.269,270 A total quinidine concentration that is >5 mg/L could be therapeutic with respect to unbound quinidine concentration. The dihydroquinidine impurity may be present in amounts that are between 10% and 15% of the labeled amount of quinidine and is believed to have similar electrophysiologic properties as quinidine.237 The 3-hydroxyquinidine metabolite has activity that is less than the parent (anywhere between 20% and 80% have been reported), is less highly bound to serum proteins, and demonstrates accumulation with chronic treatment.263,271

Cytotoxic Drugs

Although cytotoxic drugs have some characteristics that make them ideal candidates for therapeutic drug monitoring (narrow therapeutic indices and variable pharmacokinetics), they have many more characteristics that make therapeutic drug monitoring difficult or unsuitable.272,273 They lack a simple, immediate indication of pharmacologic effect to aid definition of a therapeutic range (the ultimate outcome of cure could be years). They are given in combination with other cytotoxic drugs, such that concentration versus effect relationships for any single drug is difficult to isolate. They are used to treat cancer, which is a highly heterogeneous group of diseases, each possibly having its own concentration-versus-effect relationships. In summary, cytotoxic drugs are not routinely monitored because they need more clearly defined therapeutic ranges. If ranges are established, they are usually more helpful to avoid toxicity than to define zones for efficacy.

Methotrexate

Therapeutic range

Methotrexate is the only antimetabolite drug for which serum concentrations are routinely monitored.272 It acts by blocking the conversion of intracellular folate to reduced folate cofactors necessary for cell replication. Although cancer cells are more susceptible to the toxic effects of methotrexate, healthy host cells are also affected by prolonged exposure to methotrexate. It is for this reason that leucovorin, a folate analogue that prevents further cell damage, is administered following high-dose methotrexate treatments.272 Measurements of serum methotrexate concentrations at critical times after high-dose methotrexate regimens are imperative to guide the amount and duration of leucovorin rescue treatments, thus preventing methotrexate toxicity. Institution of protocols for methotrexate serum concentration monitoring for this purpose has resulted in dramatic reductions in high-dose methotrexate-related toxicity and mortality.274

Although it is known that methotrexate concentrations must be sufficiently high to prevent relapse of the malignancy, the specific range of concentrations related to efficacy has been difficult to define.274 However, the relationship between methotrexate concentrations and toxicity has been much more clearly defined. Prolonged high concentrations of methotrexate can lead to nephrotoxicity, myelosuppression, GI mucositis, and liver cirrhosis.272,274 Serum concentration monitoring is not generally indicated when relatively low doses of methotrexate are given for chronic diseases such as rheumatoid arthritis, asthma, and psoriasis and maintenance for certain cancers.

Sample timing

The timing of samples for determination of methotrexate concentrations depends highly on the administration schedule. As one example of such a protocol, a methotrexate dose may be administered by IV infusion over 36 hours followed by a regimen of leucovorin doses administered over the next 72 hours.275 Additional or larger leucovorin doses might be given depending on the methotrexate concentrations in samples drawn at various times after the start of the methotrexate infusion. It is important that methotrexate concentrations continue to be monitored until they are below the critical concentrations (usually between 0.05 µM/L and 0.1 µM/L).272,275

Use of concentrations for dosage adjustment

Methotrexate dose adjustments and leucovorin doses are based on institution-specific protocols.

Protein binding, active metabolites, and other considerations

Methotrexate binding to albumin in serum ranges from 20% to 57%.272 Although studies have shown the unbound fraction of methotrexate to be increased by concomitant administration of nonsteroidal anti-inflammatory drugs, salicylate, sulfonamides, and probenecid, the implications for interpretation of methotrexate concentrations are probably negligible.275 The methotrexate metabolite, 7-hydroxymethotrexate, has only one-one hundredth the activity of methotrexate but may cause nephrotoxicity due to precipitation in the renal tubules.274

Other Cytotoxic Drugs

Petros and Evans provide an excellent summary of cytotoxic drugs and the types of measurements that have been used to predict their toxicity and response.274 Correlations between the response or toxicity and serum concentration or AUC versus time curve for total drug have been shown for busulfan, carboplatin, cisplatin, cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, irinotecan, paclitaxel, teniposide, topotecan, and vincristine.274,276,277 The strong correlation between busulfan AUC and bone marrow transplant outcome led the FDA to include instructions for AUC monitoring in the package insert for IV busulfan. Unbound AUC values for etoposide and teniposide, which demonstrate concentration-dependent binding, correlate more strongly with toxicity than corresponding total plasma AUC values.278 Systemic drug clearance has been predictive of response/toxicity for amsacrine, fluorouracil, methotrexate, and teniposide.274,279 Steady-state average serum concentrations or concentrations at designated postdose times have also been predictive of response/toxicity for cisplatin, etoposide, and methotrexate.274 Finally, concentrations of cytosine-arabinoside metabolite in leukemic blasts and concentrations of mercaptopurine metabolite in red blood cells have been predictive of response or toxicity for these drugs. Correlations between systemic exposure and response/toxicity for cyclophosphamide, carmustine, and thiotepa have also been reported.280 Toxicity of doxorubicin has been found to be associated with peak plasma concentrations.281 Although most studies up to this point have focused on the use of cytotoxic drug concentration measurements to minimize toxicity, future studies will increasingly focus on the use of drug concentrations to maximize efficacy.

Immunosuppressant Drugs

Immunosuppressant drugs are used for a variety of indications, including prevention of rejection in organ transplant or treatment of autoimmune diseases. Therapeutic drug monitoring is widely used to ensure adequate doses are attained and to avoid toxicity. Although this chapter discusses commonly used therapeutic ranges, individualized targets may be used based upon patient-specific factors, time from transplant, or institutional protocols.

Cyclosporine

Therapeutic range and clinical considerations

Cyclosporine is a potent cyclic polypeptide used for prevention of organ rejection in patients who have received kidney, liver, bone marrow, or heart transplants.282 It is also used for the management of psoriasis, rheumatoid arthritis, and other autoimmune diseases. The therapeutic range of cyclosporine depends highly on the specimen (whole blood or serum/plasma) and assay. Whole blood is preferred given that cyclosporine binds to erythrocytes and lipoproteins. Most transplant centers use whole blood with one of the more specific assays—high-performance liquid chromatography or immunoassays that use monoclonal antibodies (monoclonal radioimmunoassay or monoclonal fluorescence polarization immunoassay).73,283,284 The commonly cited therapeutic range for whole blood troughs using one of these specific methods is 100 to 500 mcg/L.73,285 Troughs at the higher end of this range may be desired initially after transplantation and in patients at high risk for rejection.285 The therapeutic range also depends on the specific organ transplantation procedure and the stage of treatment after surgery (higher concentrations during induction and lower concentrations during maintenance to minimize side effects) as well as comedications.73,284287 Thus, it is important that the therapeutic range guidelines established by each center be used. Although most centers still use single-trough concentrations to adjust cyclosporine doses, the area under the blood concentration versus time curve is believed to be a more sensitive predictor of clinical outcome.287 Studies that have investigated the use of single cyclosporine concentrations measured 2 hours after the dose as a surrogate for the AUC value suggest a better clinical outcome as compared with the use of single-trough concentrations.283,288,289

Cyclosporine has a narrow therapeutic index and extremely variable pharmacokinetics among and within patients. The implications of ineffective therapy and adverse reactions are serious. Thus, it is imperative that cyclosporine concentrations be monitored in all patients starting immediately after transplant surgery. The primary side effects associated with high cyclosporine blood concentrations are nephrotoxicity, neurotoxicity, hypertension, hyperlipidemia, hirsutism, and gingival hyperplasia.73,285,287 Blood cyclosporine concentrations should also be monitored when there is a dosage adjustment, signs of rejection or adverse reactions, suspected nonadherence, or the initiation or discontinuation of drugs known to induce or inhibit cyclosporine metabolism.285,287

Sample timing

Monitoring is often done immediately after surgery before a steady state is reached. Initially, concentrations may be obtained daily or every other day, then every 3 to 5 days, and then monthly. Changes in dose or initiation or discontinuation of potential enzyme inducers or inhibitors require resampling once a new steady state is reached. The half-life of cyclosporine ranges from 5 to 27 hours and depends on the particular formulation. Thus, every 3 to 5 days is generally adequate in most patients for attainment of a new steady state. Most centers continue to sample predose (trough) cyclosporine concentrations, while some are using 2-hour postdose concentrations, which appear to more closely predict total exposure to cyclosporine as measured by AUC.283,289 Multiple samples to determine the AUC are generally unnecessary.

Use of concentrations for dosage adjustment

In most cases, simple proportionality may be used for dosage adjustments. Trough or 2-hour postdose concentrations will change in proportion to the change in dose so long as the dosing interval remains the same.

Protein binding, active metabolites, and other considerations

Cyclosporine is 90% bound to albumin and lipoproteins in blood.286 Unbound fractions in blood vary widely among patients and are weakly correlated to lipoprotein concentrations in blood.286 For example, lower unbound fractions of cyclosporine have been reported in patients with hypercholesterolemia.287 Lindholm and Henricsson reported a significant drop in the unbound fraction of cyclosporine in plasma immediately prior to acute rejection episodes.290 An association between low cholesterol concentrations (and presumably high unbound fractions of cyclosporine) and increased incidence of neurotoxicity has also been reported.287 These studies suggest that efforts to maintain all patients within a certain range of total concentrations may be misleading. Routine monitoring of unbound cyclosporine concentrations is not yet feasible, given the many technical difficulties with this measurement. Instead, the clinician should cautiously interpret total concentrations of cyclosporine in situations in which altered protein binding of cyclosporine has been reported.

Other Immunosuppressant Drugs

Everolimus

Everolimus is an mTOR (mammalian target of rapamycin) kinase inhibitor that is used in the treatment of many oncologic conditions, in patients with liver and renal transplants, and in a treatment of subependymal giant cell astrocytoma (SEGA).291 Everolimus is primarily metabolized through CYP3A4 and has six known weak metabolites. The half-life is approximately 30 hours, and bioavailability decreases with high-fat meals.291,292 Whole blood concentrations should be in the range of 3 to 8 mcg/L for liver and renal transplant patients; 5 to 15 mcg/L is the reference range in patients with SEGA. In patients with liver or renal transplant, trough concentrations should be drawn 4 to 5 days after therapy initiation, dose adjustments, or discontinuation of interacting medications. In patients with SEGA, concentrations should be monitored approximately 2 weeks after initiation or dose adjustment; when interacting medications are initiated, discontinued, or changed; with changes in everolimus formulation; or with changes in liver function. When a maintenance dose has been attained, trough concentrations should be monitored every 6 to 12 months. More frequent monitoring of 3 to 6 months is suggested if a patient’s body surface area is fluctuating. Everolimus is 74% protein-bound.291

Mycophenolic acid

Mycophenolate mofetil, the prodrug of mycophenolic acid, is often used in combination with cyclosporine or tacrolimus with or without corticosteroids in patients who have received transplant and may be used alone in patients with various autoimmune diseases.287 Although troughs of mycophenolic acid may be monitored (plasma concentrations between 2.5 and 4 mg/L are targeted with good success), AUC values appear to be better predictors of postoperative efficacy (avoidance of acute rejection).289,293,294 Reliable measurements of AUC may be determined with as few as three samples (trough, 30 minutes postdose, and 120 minutes postdose) with a desired target AUC range of 30 to 60 mg × hr/L.293 The half-life of mycophenolic acid is approximately 17 hours. Thus, a new steady state is attained approximately 3 days after a dose change or the addition/discontinuation of drugs that affect the metabolism of mycophenolic acid. Mycophenolic acid is 98% bound to plasma proteins, and the unbound fraction is greatly influenced by changes in albumin concentration, displacement by metabolites, renal failure, and hyperbilirubinemia.283,293 Several groups of investigators suggest that unbound mycophenolic acid concentrations should be monitored when altered binding is suspected.287,293296 There is evidence that unbound mycophenolic acid concentration may be a better predictor of adverse effects than total concentration.295,297

Sirolimus

Sirolimus is a macrolide antibiotic with potent immunosuppressant activity. When used in combination with cyclosporine and corticosteroids, trough blood concentrations of 5 to 15 mcg/L are generally targeted.285 With whole blood sampling, therapeutic concentrations measure 10 to 15 mcg/L with concomitant calcineurin inhibitors, and higher ranges of 15 to 25 mcg/L are targeted without calcineurin inhibitors.298 It has a relatively long half-life (62 hours), and a new steady state is not attained in many patients until at least 6 days after dose adjustments or the addition or discontinuation of interacting drugs.285 At present, trough concentrations are used for monitoring because they correlate well with AUC.283

Tacrolimus

Tacrolimus is a macrolide antibiotic with immunosuppressant activity and is generally used in combination with other immunosuppressant drugs. Trough blood concentrations of tacrolimus as high as 20 mcg/L are targeted during initial treatment and gradually decrease to between 5 and 10 mcg/L during maintenance therapy, often after 12 months, and are generally determined by indication and institution-specific protocols.289 Toxicities to tacrolimus are similar to those with cyclosporine, including nephrotoxicity and neurotoxicity.285,299 The unpredictable and variable extent of tacrolimus bioavailability (5% to 67%) contributes to the need for monitoring of this drug.299 The advent of a once-daily extended-release formulation produced with advanced drug-delivery systems can enhance bioavailability and maintain stable serum concentrations over 24 hours.300 Differences in pharmacogenomics (related to the CYP3A4*22 allele) have been associated with altered pharmacokinetics.301 Monitoring should always be done after changes in dose or initiation/discontinuation of enzyme-inducing or inhibiting agents. The half-life of tacrolimus ranges from 4 to 41 hours for both immediate- and extended-release formulations, and a new steady state is attained after approximately 3 to 5 days.285,287 Although trough concentrations are still the method of choice for monitoring, a second concentration might be needed if Bayesian approaches to dosage individualization are used.289,302 Some evidence suggests the window for obtaining a blood sample for those patients receiving the extended-release formulation may be wider (±3 hours of the dose), which may allow more flexibility and reduce waste from improperly timed concentrations.300 Tacrolimus exhibits linear elimination behavior; thus, an increase in the daily dose is expected to result in a proportional increase in the steady-state trough concentration. Tacrolimus is 75% to 99% bound to plasma proteins (albumin, α-1-glycoprotein, lipoproteins and globulins).287,299 Reports of lower unbound serum concentrations of tacrolimus during episodes of rejection lead one to be cautious with interpretation of total tacrolimus concentrations in patients with suspected alterations in protein binding.297

Psychotropics

Tricyclic Antidepressants (Amitriptyline, Nortriptyline, Imipramine, Desipramine)

Therapeutic ranges

Although tricyclic antidepressants (TCAs) continue to be used for the treatment of depression, their use has significantly declined in favor of newer antidepressants.303 The therapeutic ranges of amitriptyline, imipramine, desipramine, and nortriptyline are well defined for depression; however, they are not routinely used for other off-label indications, such as sleep or pain.25,304,305 Desipramine and nortriptyline are also active metabolites of imipramine and amitriptyline, respectively.

When imipramine is administered, combined serum concentrations of imipramine and desipramine that are considered therapeutic but not toxic are between 180 and 350 mcg/L.304,305 Combined concentrations above 500 mcg/L are extremely toxic.305 When desipramine is administered, concentrations between 115 and 250 mcg/L are frequently associated with therapeutic effect.304,305 When amitriptyline is administered, combined serum concentrations of amitriptyline and nortriptyline should be between 120 and 250 mcg/L.304 Combined concentrations above 450 mcg/L are not likely to produce an additional response and are associated with cardiotoxicity and anticholinergic delirium.305 The therapeutic range of nortriptyline is the most firmly established of these four drugs; target serum concentrations after nortriptyline administration are between 50 and 150 mcg/L.304306

The most common side effects of the TCAs are anticholinergic in nature.304 Toxicities seen at higher concentrations include cardiac conduction disturbances, seizures, and coma.304 For all of the TCAs, these toxic effects occur at serum concentrations that are approximately five times those needed for antidepressant efficacy.11 Indications for monitoring include suspected nonadherence or inadequate response, suspected toxicity, and suspected unusual or altered pharmacokinetics (seen in children and elderly persons and with drug interactions).

The TCAs in general are highly bound to serum proteins.303 Thus, one would expect unbound TCA serum concentrations to be much better predictors of response than total concentrations, particularly in populations suspected to have unusually high or low serum binding. Until now, studies that have attempted to examine this have not been able to clarify relationships between response and total serum concentrations based on variable protein binding. The TCAs are extensively metabolized and undergo significant first-pass metabolism. Although the primary active metabolites have been identified and are separately measured, other active metabolites can accumulate in some circumstances and affect the response at a given parent drug concentration.307

Other Antidepressants: Selective Serotonin Reuptake Inhibitor, Serotonin Norepinephrine Reuptake Inhibitor, Monoamine Oxidase Inhibitors

Assays have been developed to document the serum concentrations observed following the administration of other cyclic antidepressants as well as the selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and norepinephrine reuptake inhibitors.11,308,309313 Although reference ranges have been established, there does not appear to be any compelling reason for routine monitoring of these drugs given their relatively wide therapeutic indices and more favorable side effect profiles. Because 50% of patients not achieving optimal relief from symptoms of depression, some clinicians advocate the use of serum concentration monitoring in patients who do not initially respond to identify nonadherence or unusually low serum concentrations.11,25,307,314

Lithium

Therapeutic range

Lithium is a monovalent cation used for the treatment of bipolar disorder and the manic phase of affective disorders, and it is somewhat effective in the treatment of refractory depression.314 The concentration units for lithium are expressed as milliequivalent/liter, which is the same as millimole/liter. Although the overall therapeutic range for treatment of bipolar disorder is commonly cited as 0.5 to 1.2 mEq/L, there appear to be two distinct ranges used in practice, depending on the stage of therapy.26,305 For acute management of manic episodes, the therapeutic range of 0.8 to 1.2 mEq/L is desired, going up to 1.5 mEq/L if necessary.73,315,316 For maintenance treatment, the therapeutic range of 0.6 to 1 mEq/L or 1 to 1.2 mEq/L is usually recommended.73,310,315,317 In elderly patients, target therapeutic concentrations are as low as 0.2 mEq/L.318 Serum concentrations >1.5 mEq/L are associated with fine tremors of the extremities, GI disturbances, muscle weakness, fatigue, polyuria, and polydipsia. Concentrations >2.5 mEq/L are associated with coarse tremors, confusion, delirium, slurred speech, and vomiting. Concentrations >2.5 to 3.5 mEq/L are associated with seizures, coma, and death.304 It is important to point out that the values for the therapeutic ranges are based on samples obtained at a specific time during the day—just before the morning dose and at least 12 hours after the evening dose for patients on a BID or TID regimen.315,319

Most clinicians require that every patient taking lithium be regularly monitored, which is cost effective considering the potential avoidance of toxicity.73,306 Specific indications for lithium concentration monitoring include evaluation of nonadherence, suspicion of toxicity, confirmation of the concentration associated with efficacy, and any situation in which altered pharmacokinetics of the drug is anticipated (drug–drug interactions, pregnancy, children, geriatric patients, and fluid and electrolyte imbalance). Despite the strong indication for lithium monitoring in all patients, 37% of lithium users on Medicaid did not have serum drug concentrations monitored.320

Sample timing

The half-life of lithium ranges from 18 to 24 hours, and steady state is reached within a week of therapy.315 However, 2 to 3 weeks of treatment may be required after that before the full response to the drug can be assessed.315 When initiating lithium therapy, it is recommended that serum concentrations be measured every 2 to 3 days (before a steady state is reached) to ensure that concentrations do not exceed 1.2 mEq/L during that time.73 Because of the extreme variability of serum lithium concentrations during the absorption and distribution periods, the current standard of practice is to draw all samples for lithium serum concentration determination 12 hours after the evening dose, regardless of whether a twice- or thrice-daily dosing schedule is used. For example, the time for blood sampling for a patient on a 9 a.m./3 p.m./9 p.m. schedule would be right before the 9 a.m. dose.73 The timing of blood samples for a patient taking once-daily lithium is less clear given the greater degree of serum lithium concentration fluctuation with this dosing method.315

Use of concentrations for dosage adjustment

Lithium exhibits linear elimination behavior, and proportionality can be assumed when dosage adjustments are made. The assumption of linearity is the basis for several dosing methods that are used for initiating lithium therapy in patients. The Cooper method involves drawing a sample for lithium analysis 24 hours after a first dose of 600 mg.44 The resulting concentration, believed to provide a reflection of the drug’s half-life, is used with a nomogram that indicates the optimal maintenance regimen. The Perry method requires that two concentrations be drawn during the postabsorption, postdistribution phase after a first dose of lithium.45 These two concentrations are used to determine the first-order elimination rate constant, which can then be used to determine the expected extent of lithium accumulation in the patient. The maintenance regimen required to attain a desired target lithium concentration in that patient can then be determined. Population-pharmacokinetic, dosing–initiation methods (Bayesian) can also be used.73

Protein binding, active metabolites, and other considerations

Lithium is not bound to serum proteins, nor is it metabolized.

Antipsychotics

The existence of well-defined therapeutic ranges for most antipsychotic drugs remains controversial.321323 There is growing interest in therapeutic drug monitoring of antipsychotics and several drugs have more established therapeutic drug monitoring guidance.25,324326 The AGNP-TDM Expert Consensus Guidelines: Therapeutic Drug Monitoring in Psychiatry make several recommendations for serum drug concentration monitoring for several antipsychotics, including haloperidol, perphenazine, fluphenazine, amisulpride, clozapine, olanzapine, and risperidone. The focus of therapeutic drug monitoring for antipsychotics is for the prevention of adverse effects, especially extrapyramidal effects during dose titration for effect with an emphasis on quality of life rather than a concern for toxicity.25 Additional considerations include assessment of adherence or lack of response at maximal doses. Clozapine would be the only exception because toxicity can be seen at the upper end of the therapeutic range and the incidence of seizures with clozapine directly correlates with plasma concentrations.25,327 Although there is a range of interpatient variability related to clozapine pharmacokinetics, Rajkumar and colleagues found that in patients with treatment-resistant schizophrenia, increasing doses of clozapine, caffeine intake, and VPA administration were most closely associated with serum clozapine concentrations.325 Reference ranges for other antipsychotic drugs are primarily based on average serum concentrations observed during chronic therapy.306,310 One difficulty in establishing clear therapeutic range guidelines and subsequent dose adjustments is that chronicity of illness and duration of antipsychotic drug exposure can shift the therapeutic range; separate therapeutic ranges may need to be developed depending on duration of illness. Furthermore, many medications are used for various psychotic indications in which dosing ranges and therapeutic concentrations may differ.

FUTURE OF THERAPEUTIC DRUG MONITORING

Drug assays are rapidly improving with regard to specificity, sensitivity, speed, and convenience. Methods that separate drug enantiomers may help to elucidate therapeutic ranges for compounds administered as racemic mixtures.328 Capillary electrophoresis-based assays will be increasingly used in clinical laboratories because of their low cost, specificity, use for small sample volumes, and speed.329 Methods for measurement of drugs in hair samples are being proposed for assessment of long-term drug adherence.330 Implanted amperometric biosensors, currently used for glucose monitoring, may be useful for continuous monitoring of drug concentrations.331 Subcutaneous microdialysis probes may also be useful for continuous drug monitoring, particularly because they monitor pharmacologically active unbound drug concentrations.332 Point-of-care assay methods, currently used in private physician offices, group practices, clinics, and emergency departments, could eventually be used in community pharmacies in the future.333,334

Therapeutic drug monitoring of the near future may also involve determination of genotypes, characterization of proteins produced in particular diseases (proteomics), and analysis of drug metabolite profiles (metabonomics).335,336 Pharmacogenomics and related sciences may help to identify those subsets of patients who will be nonresponders or toxic responders and help to determine appropriate initial doses and patients who will benefit most from therapeutic drug monitoring. Such testing would not require special sample timing, might be possible using noninvasive methods (eg, hair, saliva, and buccal swabs), and would need to be done only once because the results would apply over a lifetime. This type of testing may help patients receive the best drug for the indication and rapid individualization of drug dosage to achieve desired target concentrations.32,33,335,337 The addition of this testing will likely result in an increased demand for new types of tests from clinical laboratories currently involved in routine therapeutic drug monitoring.

There is a movement to change the terminology and practice of therapeutic drug monitoring to target concentration strategy, concentration intervention, and therapeutic drug management.46,338 Critics of the therapeutic drug monitoring terminology claim that it suggests a passive process that is concerned only with after-the-fact monitoring to ensure that concentrations are within a range without proper regard to evaluating the response to the drug in an individual patient.338 Target concentration intervention is essentially a new name for a process that has been used by clinical pharmacokinetics services for years and involves the following steps: (1) choosing a target concentration (usually within the commonly accepted therapeutic range) for a patient; (2) initiating therapy to attain that target concentration using best-guess population pharmacokinetic parameters; (3) fully evaluating the response at the resulting steady-state concentration; and (4) adjusting the regimen as needed using pharmacokinetic parameters that have been further refined by use of the drug concentration measurement(s).

The desire for positive clinical responses with new biologic agents, such as monoclonal antibodies, warrants further investigation as patients seek individualized and expensive treatment options. Studies do not currently recommend routine monitoring, but clinicians should be aware of further development in this area.339,340 Methods to improve the therapeutic drug monitoring process itself are needed. Every effort should be made to focus on patients who are most likely to benefit from therapeutic drug monitoring, and minimize the time and money spent on monitoring that provides no value.8 The biggest problems with the process continue to be lack of education, communication, and documentation.5,23 Approaches to changing clinician behavior with regard to appropriate sampling and interpretation include educational sessions, the formation of formal therapeutic drug monitoring services, multidisciplinary quality improvement efforts, and the computerization of requests for drug concentration measurement samples.341 Pharmacists will continue to play a pivotal role in the education of licensed independent practitioners and others involved in the therapeutic drug monitoring process. Future studies that evaluate the effect of therapeutic drug monitoring on patient outcomes will likely use quality management approaches.342

LEARNING POINTS

1. A female patient who was diagnosed with complex partial seizures was initiated on VPA, 750 mg/day. She returns to the clinic after 4 weeks and reports that she has not had any seizures since taking the VPA. There are no signs or symptoms consistent with VPA toxicity. Why should a serum VPA concentration be measured in this patient?

ANSWER: Given the endpoint of therapy is the absence of something (seizures in this case), there is no way to ensure that the patient is taking enough VPA. Some types of seizures occur infrequently, and it is possible that the patient’s serum VPA concentration is low and she simply has not had a seizure yet. It is important to ensure that the concentration is within the therapeutic range of 50 to 100 mg/L (for patients with normal serum albumin concentrations) before assuming the patient is adequately protected from future seizure activity.

2. A 24-year-old female patient with hypoalbuminemia has been initiated on phenytoin for treatment of generalized tonic-clonic seizures. A serum phenytoin concentration is measured and reported as 16 mg/L. The patient reports that she has not experienced any seizures since starting the phenytoin, but she has noticed weakness and blurry vision since then. Nystagmus is observed on physical exam. The laboratory reports a serum albumin concentration of 2.5 g/dL (normal is 3.5 to 5 g/dL). How do you interpret the phenytoin concentration?

ANSWER: The target therapeutic range for phenytoin concentrations is reported as 10 to 20 mg/L. This range, however, assumes an albumin concentration that is within the normal range. A patient with abnormally low albumin concentrations is likely to show toxicity when phenytoin concentrations are between 10 and 20 mg/L. Due to the low albumin concentrations, the unbound concentration of phenytoin is high. Therefore, it is likely in this case that the dose of phenytoin is too high, thus accounting for the ataxia and nystagmus. A phenytoin concentration at the low end of the usual therapeutic range (or even below) would be a more appropriate goal. Furthermore, the use of free, or unbound, phenytoin concentrations to establish correlation may be of benefit.

3. A 60-year-old male patient with normal renal function was initiated on oral digoxin 0.25 mg every morning for treatment of supraventricular arrhythmias. He returns to his primary care physician 1 month later for an 8 a.m. appointment. A blood sample, drawn at 8:30 a.m., reveals a digoxin serum concentration of 2.9 mcg/L. There are no signs or symptoms of digoxin toxicity. On further inquiry, the patient reveals that he took his digoxin dose at 7:30 a.m. that morning. A repeat sample drawn right before the next digoxin dose is 1.2 mcg/L. What is the reasoning for the discrepancy in the two reported digoxin concentrations?

ANSWER: This discrepancy illustrates the importance of blood sample timing relative to the intake of the last drug dose. The initial serum digoxin concentration in this case is above the upper limit generally defined for patients with atrial arrhythmias (1.2 mcg/L) and might lead to the conclusion that the daily digoxin dose is excessively high. However, the sample should have been drawn sometime between 6 hours after the dose and right before the next dose, allowing adequate time for digoxin in blood to have equilibrated with digoxin in myocardial tissue. Significant resources are wasted by inappropriate timing of blood samples for digoxin measurements, and incomplete documentation of dose or blood sample timing.

4. A 35-year-old male patient with a history of lymphoma is admitted due to MRSA bacteremia and is receiving IV vancomycin therapy (dosed at 1,750 mg [18 mg/kg] IV every 8 hours). His renal function is normal and he is currently hemodynamically stable. A vancomycin concentration 7.5 hours after initial dose is drawn from his central line and reveals a concentration of 52 mg/L. The clinical pharmacy specialist decides to hold the next dose and orders a repeat concentration (a total of 16 hours after dose), which reveals a concentration of <2 mg/L. What is/are reason(s) for the initial elevated vancomycin concentration?

ANSWER: Appropriateness of drawn concentrations is key in the interpretation of concentrations. There are several reasons why a concentration may not make sense. Dosed appropriately, it is expected that the vancomycin concentration in this patient would be lower than what was observed, namely given the dose is appropriate for this younger patient with normal renal function and who does not have any signs of impending hemodynamic instability. One possible explanation for the higher-than-expected concentration is the fact that the sample was drawn from the central line. Some reports note falsely elevated concentrations when drawn from central lines, and therefore the recommendation is to draw drug concentration samples using peripheral sites instead. Additionally, it is possible that the sample was drawn from a line that was not flushed prior to sample withdrawal. Finally, there could be patient-specific factors that can contribute to the higher-than-expected concentrations or concomitant use of nephrotoxic agents.

5. A 47-year-old male patient with a history of bipolar I and recent new diagnosis of reduced ejection fraction heart failure presents to the emergency department with new-onset diarrhea, ataxia, confusion, and polyuria. His home medications include carvedilol 6.25 mg BID, lisinopril 2.5 mg daily, furosemide 20 mg daily, and lithium ER 300 mg BID. The physician orders a lithium concentration, which results as 2.1 mEq/L. What is/are the reason(s) for the patient’s elevated lithium concentration?

ANSWER: The patient had a recent addition of a diuretic (furosemide) and angiotensin-converting enzyme inhibitor (lisinopril), which can increase lithium concentrations through the reduced elimination of lithium. This case highlights the importance of drug interactions on serum concentrations of certain medications, which should be reviewed during the prescribing and dispensing process to ensure proper monitoring and adjustment.

ACKNOWLEDGMENTS

The authors would like to acknowledge the contributions of Dr. Jaclyn A. Boyle and Dr. Janis J. MacKichan, who helped author this chapter in previous editions of this textbook.

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