Therapeutic Drug Monitoring Clinical Guide FOURTH EDITION

DIAGNOSTICS

1 Therapeutic Drug Monitoring Clinical Guide FOURTH EDITION

Authors Mike Hallworth, MA, MSc, FRCPath Former Consultant Biochemist Royal Shrewsbury Hospital United Kingdom Ian Watson, MSc, PhD, FRCPath Former Consultant Biochemist and Toxicologist University Hospital Aintree Liverpool, United Kingdom

Editors of the David Holt, DSc, PhD Third Edition Susan Tett, PhD, BPharm (Hons), MPS Steven H. Wong, PhD, DABCC (TC), FACB

2 CONTENTS

THERAPEUTIC DRUG MONITORING ...... 5 RUFINAMIDE ...... 81 WHY IS TDM NECESSARY? ...... 6 TIAGABINE ...... 83 WHICH DRUGS SHOULD BE MONITORED? ...... 8 TOPIRAMATE ...... 85 PRACTICAL CONSIDERATIONS ...... 10 VALPROATE ...... 87 CALCULATION OF DOSAGE ADJUSTMENT ...... 15 VIGABATRIN ...... 89 OTHER APPROACHES TO OPTIMIZING THERAPY — ZONISAMIDE ...... 91 PHARMACOGENETICS AND BIOMARKERS ...... 17 ANTIFUNGALS ...... 94 EFFECTIVENESS OF TDM – DOES IT HELP PATIENTS? ...... 19 POSOCONAZOLE/VORICONAZOLE ...... 95 REFERENCES ...... 21 ANTINEOPLASTICS ...... 98 WEBSITES ...... 23 BUSULFAN ...... 99 DRUG DATA PROFILES ...... 24 METHOTREXATE ...... 101 PREFACE ...... 24 ANTIRETROVIRALS ...... 104 ADDICTION THERAPEUTICS ...... 28 ANTIRETROVIRALS ...... 105 BUPRENORPHINE ...... 29 BRONCHODILATOR, ANALEPTIC ...... 108 METHADONE ...... 31 THEOPHYLLINE ...... 109 ANALGESICS ...... 34 CAFFEINE ...... 111 ACETAMINOPHEN (PARACETAMOL) ...... 35 CARDIAC AGENTS ...... 114 ACETYLSALICYLIC ACID (ASPIRIN) ...... 37 ANTI-ARRHYTHMICS MORPHINE ...... 39 AMIODARONE ...... 115 ANTIBIOTICS ...... 42 DISOPYRAMIDE ...... 117 AMINOGLYCOSIDES FLECAINIDE ...... 119 AMIKACIN ...... 43 LIDOCAINE ...... 121 GENTAMICIN ...... 45 CARDIAC GLYCOSIDES TOBRAMYCIN ...... 47 DIGOXIN ...... 123 OTHER ANTIBIOTICS IMMUNOSUPPRESSIVE AGENTS ...... 126 TEICOPLANIN ...... 49 CICLOSPORIN/CYCLOSPORINE ...... 127 VANCOMYCIN ...... 51 MYCOPHENOLATE ...... 129 ANTIEPILEPTICS ...... 54 SIROLIMUS ...... 131 CARBAMAZEPINE ...... 55 TACROLIMUS ...... 133 CLONAZEPAM ...... 57 PSYCHOACTIVE AGENTS ...... 136 ESLICARBAZEPINE ACETATE ...... 59 TRICYCLIC ANTIDEPRESSANTS ETHOSUXIMIDE ...... 61 AMITRIPTYLINE ...... 137 FELBAMATE ...... 63 OTHERS GABAPENTIN ...... 65 CLOZAPINE/OLANZAPINE ...... 139 LACOSAMIDE ...... 67 FLUOXETINE ...... 141 LAMOTRIGINE ...... 69 HALOPERIDOL ...... 143 LEVETIRACETAM ...... 71 LITHIUM ...... 145 OXCARBAZEPINE ...... 73 GLOSSARY ...... 147 PHENOBARBITAL/PRIMIDONE ...... 75 COMMON TRADE NAMES ...... 150 PHENYTOIN/FOSPHENYTOIN ...... 77 PREGABALIN ...... 79

3 4 THERAPEUTIC DRUG MONITORING during the 1960s and the development of the fundamental concepts of pharmacokinetics and pharmacodynamics. Therapeutic drug monitoring (TDM) is the use of drug concentration measurements in body fluids as an aid to the management of drug The scene was thus set for the surge of publications in the early 1970s therapy for the cure, alleviation or prevention of disease.1 It has on improving individualization of therapy by the monitoring of drug long been customary to adjust the dosage of drugs according to the concentration and appropriate adjustment of dose – the beginnings of characteristics of the individual being treated and the response TDM as we know it. The remaining barrier to widespread adoption obtained. Physicians have been most ready to do this when the of the concept — the availability of appropriate analytical methods — pharmacological response can be easily established by clinical means was removed during the 1970s by the development of commercially (e.g., antihypertensive drugs, analgesics, hypnotics) or by laboratory available homogeneous immunoassays for therapeutic drugs. The markers (e.g., anticoagulants, hypoglycemic agents, lipid-lowering ability to provide accurate and precise results simply and quickly drugs, hormone preparations). If there is a wide margin between the resulted in the explosive growth of TDM applications in the second MONITORING DRUG THERAPEUTIC toxic dose and the therapeutically effective dose, then monitoring half of the 1970s. may be unnecessary (e.g., penicillins). However where this is not the case and the drug’s action cannot readily be assessed clinically (e.g., in WHY IS TDM NECESSARY? the prophylaxis of seizure or mania) or when toxic effects cannot be As stated above, there are a number of drugs for which desired (or detected until severe or irreversible (e.g., aminoglycoside antibiotics, toxic) effects cannot readily be assessed clinically, but are related to immunosuppressants), then dosage individualization is much more the amount of drug in the body. In such cases, the logical approach difficult, though no less important. TDM now has an established place to control the effect of the drug is to limit the amount that is given to in enabling optimization of therapy with such agents. However, it must the patient. Pragmatically, using standard doses that will produce a be emphasized that clinical and other criteria remain important and satisfactory response in the majority of patients can achieve this. Such TDM should never be the sole basis for individualization of therapy. an approach has been widely used in medicine and is undoubtedly TDM has been established for a tightly defined group of drugs. It must effective for a large number of drugs (e.g., penicillins). The rapid be considered as a process where it (1) begins with a clinical question, development of pharmacogenomics is changing the crude “one dose (2) continues by devising a sampling strategy to answer that question, fits all” paradigm and will be discussed further later in this chapter. (3) determines one or more drug or metabolite concentrations using a For many (but not all) drugs, the primary determinant of clinical suitable method, and (4) interprets the results appropriately. response is the concentration that can be achieved at the site of action TDM has been routinely practised in clinical laboratories since the (the cell receptor, locus of infection, etc.). Often, wide variations in mid-1970s, following initial research work showing its potential value. drug concentration above a minimum or threshold level will make Buchthal2 showed in 1960 that there was a relationship between little difference to the clinical effect. However, for some drugs the plasma concentrations of phenytoin in patients being treated for desired effect (and various unwanted effects) may be very sensitive to epilepsy and the degree of seizure control attained. Baastrup and the drug concentration at a given time. Dr. Bernard Brodie suggested Schou demonstrated the relationship between plasma concentration in a keynote lecture given in 1967 that the marked heterogeneity of and pharmacological effect for lithium in 1967.3 This work coincided biological species with regard to drug metabolism meant that it would with the rise of clinical pharmacology as an independent discipline be preferable to relate drug effects to the plasma drug concentration rather than the dose.

5 6 BACK TABLE TO OF CONTENTS The problem with an approach based on standard dosing for some drugs PROCESSES INVOLVED IN DRUG HANDLING is illustrated in Figure 1, which shows the frequency distribution of Figure 2: Processes Dose Other involved in drug handling. plasma phenytoin concentrations among 200 ambulatory patients prescribed tissues chronically treated with 300 mg daily.4 If the clinically-accepted target range for phenytoin is 5-20 mg/L (20-80 μmol/L), a large adherance distribution number of patients receiving the standard dose have plasma phenytoin Dose Drug in Active EFFECT concentrations below those said to be effective. Conversely, a minority taken blood site have concentrations significantly above the generally accepted range and may be exhibiting symptoms of toxicity. The steady-state elimination phenytoin concentration in a given patient clearly cannot be predicted Excreted/ from the dose. This is due to interindividual variation in the processes inactivated drug THERAPEUTIC DRUG MONITORING DRUG THERAPEUTIC that are involved between the prescribed drug and that drug achieving PHARMACOKINETICS PHARMACODYNAMICS an effective concentration at its site of action. These processes are summarized in Figure 2 and may be conveniently divided into discussion of pharmacokinetic and pharmacodynamic processes is pharmacokinetic factors and pharmacodynamic factors. Essentially, outside the scope of this monograph, and standard texts may be pharmacokinetics may be defined as what the body does to drugs (the consulted.5 processes of absorption, distribution, metabolism and excretion) and pharmacodynamics as what the drugs do to the body (mechanisms of WHICH DRUGS SHOULD BE MONITORED? drug action and biochemical/pathophysiological effects such as tissue Drug concentration monitoring is neither feasible nor warranted for responsiveness, presence of other drugs and disease states). A detailed all drugs. Serum concentration monitoring is valuable in measuring the clinical effectiveness of drugs in the following circumstances:

DISTRIBUTION OF PLASMA PHENYTOIN CONCENTRATIONS When there is poor correlation between dose and clinical effect 20 Figure 1: Frequency Self-evidently, if the dose is a good predictor of the pharmacological distribution of plasma effect, then the dose can be used to monitor therapy and TDM is not phenytoin concentrations in normally required. TDM is primarily of potential benefit where there 15 200 adult outpatients taking phenytoin (300 mg daily). is poor correlation between dose and effect (wide interindividual (Possibly partially influenced pharmacokinetic variation). 10 by CYP2C9 and CYP2C19 variations.) Koch-Weser J. When there is a narrow concentration interval between therapeutic % of patients Serum drug concentrations and toxic effects 5 in clinical perspective. Richens, A., Marks V. (eds). The therapeutic index (therapeutic ratio, toxic-therapeutic ratio) Therapeutic Drug Monitoring. Edinburgh: Churchill for a drug indicates the margin between the therapeutic dose and 0 10 20 30 40 50 Livingstone 1981:1-22 (with the toxic dose: the larger, the better. For most patients (with the Plasma Phenytoin (mg/L) permission). exception of those who are hypersensitive) penicillin has a very high therapeutic ratio. It is safe to use in much higher doses than

7 8 BACK TABLE TO OF CONTENTS necessary to treat the patient satisfactorily, with no necessity to its clinical effects are slightly easier to assess, in adults at least, check the concentration attained. However, for other drugs (e.g., its clinical use continues to decline. A number of other frequently anticoagulants, aminoglycoside antibiotics, antineoplastic drugs, monitored drugs fail to meet one or more criteria completely and the immunosuppressants, cardiac glycosides) the margin between effectiveness of TDM as an aid to management is severely reduced. desirable and toxic dose is very small and monitoring is valuable in The concentration-effect relationship for carbamazepine is not achieving effective concentrations without systemic toxicity. always straightforward because of the presence of active metabolites. Digoxin fulfills most of the criteria, but with some doubt about the When there are no good clinical markers of effect concentration-effect relationship. TDM is clearly of little value when the desired effect and any associated adverse effects can readily be assessed by simple clinical The evidence for many drugs is based more on practical experience measurements (e.g., blood pressure in the case of anti-hypertensive than well-designed studies. However, when the immunosuppressant agents or plasma glucose concentration for oral hypoglycemic drugs). drug cyclosporine was introduced into clinical practice, considerable MONITORING DRUG THERAPEUTIC effort was invested in demonstrating the beneficial outcomes When plasma concentration shows a good correlation with associated with effective TDM. This has provided a model for clinical effect subsequent immunosuppressants (e.g., tacrolimus, sirolimus and This is the fundamental condition that must be fulfilled if TDM is to mycophenolate). Similar evidence is accumulating to support the be practical for a particular drug. The concentration measurements benefit of TDM for antiretroviral and antifungal drugs. must give accurate information about the biological effect, otherwise The drugs listed in this monograph are the main drugs for which they are of no value and may even be misleading. Plasma or blood TDM has been shown to have clinical value. concentrations should correlate well with effect or toxicity, and thereby define the therapeutic window and allow titration of the dose PRACTICAL CONSIDERATIONS to achieve a given effect. Demonstration of a close concentration- Once the narrow range of drugs for which therapeutic drug effect relationship requires that (1) there is minimal interindividual monitoring can provide useful information has been defined, it pharmacodynamic variability, (2) no active metabolites contribute to should not be assumed that TDM is therefore required for all patients the biological effect but are not measured in the assay system, and receiving these drugs. For a concentration measurement to be applied (3) the drug has a reversible mode of action at the receptor site. This last effectively to improve patient care, four criteria must be satisfied on relationship ensures that the intensity and duration of the response is each occasion a sample is taken. These are: temporally correlated with the drug concentration at the receptor site. (The exception to this general rule may be some anticancer agents, A rational indication for the request (a clinical question) where the action of the drug is irreversible but an index of the body’s The first essential for making effective use of any laboratory test total exposure to the drug may predict subsequent response.) is to be clear from the onset which question is being asked. This is The list of drugs that fulfill the criteria listed above is small. particularly true of TDM requests, and the widespread failure to Phenytoin and lithium are probably the best and earliest examples of define the indication for analysis is at the root of most of the problems drugs that meet all the criteria and for which TDM is essential. The faced by TDM services. If the question is not clear, or if it is the wrong aminoglycoside antibiotics, chiefly gentamicin and tobramycin, also question, then the answer is of little value. qualify on all counts. Theophylline meets most criteria. Although

9 10 BACK TABLE TO OF CONTENTS The main reasons for measuring drugs in plasma may be summarized as: taken to reach steady state is determined by the elimination half- • To ensure that sufficient drug is reaching the drug receptor to life of the drug. In practice, samples are taken after drug dosing has produce the desired response (the onset of which may be delayed) continued for at least four half-lives. • To ensure that drug (or metabolite) concentrations are not so high The plasma concentration after 3.3 half-lives is 90 percent of the as to produce symptoms or signs of toxicity predicted steady state. This may be taken as the minimum time for • To guide dosage adjustment in clinical situations in which the sampling after starting the drug or changing the dose. For drugs with pharmacokinetics are changing rapidly (e.g., in neonates, children a long half-life (e.g., digoxin, phenobarbitone), two weeks or more or patients in whom hepatic or renal function is changing) maybe required before steady-state samples can be taken, especially if • To define the pharmacokinetic parameters and concentration- renal function is poor and the drug is renally excreted (e.g., digoxin). effect relationships of new drugs In the neonate, the rapidly changing clinical state, degree of hydration

and dosage requirements make the idea of steady state a theoretical MONITORING DRUG THERAPEUTIC Accurate patient information concept rather than an attainable goal in many cases. There is little Accurate information about the patient (name, identification number, value in delaying concentration measurements for such a hypothetical age, gender and pathology), the drug therapy (dose, formulation steady state to be established. and route of administration, length of therapy, date and time of last dose), the specific question to be investigated and the date and time A further requirement for many drugs is to take samples at of the sample are essential for proper interpretation. These should the appropriate time following the last dose. Serum digoxin be provided on the request form. Additional information such as the concentrations do not reflect tissue concentrations for at least six patient’s weight, renal and hepatic function and other prescribed hours following dosing due to continuing distribution, and specimens medication may also be required in many circumstances. These for digoxin analysis should not be collected during this period. requirements have led many hospitals to design request forms The size of the fluctuations in plasma concentration between doses specifically for TDM analyses. The increasing use of computerized obviously depends on the dosage interval. Frequent dosing avoids order-entry systems means that essential information can be made large peaks and transient toxic effects. But this practice is unpopular mandatory at the point of requesting. These can be linked to rule bases with patients, difficult to comply with, and more likely to lead to to ensure appropriate requesting and to improve use of TDM services. medication errors. Less frequent dosing gives rise to large fluctuations in concentration. To some extent, these opposing considerations can An appropriate specimen be reconciled with the use of sustained-release preparations. An appropriate specimen is obviously a prime requirement for effective TDM. Serum or plasma samples are normally used, although There is no single optimum time for taking samples in relation to dose. whole blood is the preferred matrix for many immunosuppressive The most reproducible time to take measurements is immediately pre- drugs (e.g., cyclosporine) as the drug is concentrated in red cells. dose (trough concentration), when the lowest levels in the cycle will be obtained. This is best if an indication of drug efficacy is required. Timing of sample-taking is also important. For TDM to be This sample will show the least between-sample variability in patients meaningful,the patient should be in steady state on the present dose on chronic therapy. The use of peak and trough concentrations for of the drug. However, when suspected toxicity is being investigated, detecting toxicity of aminoglycoside antibiotics has become less waiting to attain steady state is clearly contraindicated. The time

11 12 BACK TABLE TO OF CONTENTS relevant with once-daily dosing regimens, but sampling at two hours the patient’s symptoms rather than to get drug levels into a post-dose for cyclosporine has become a common and effective TDM particular range. technique. This type of sampling in the absorption/distribution The target range is a synthesis of two concepts — the minimum phase is highly sensitive to accurate determination of sampling time effective concentration for a drug and the maximum safe in relation to dose. The average steady-state concentration may be concentration. Between these limits, the majority of patients should obtained by taking samples approximately midway between doses, or experience maximum therapeutic benefit at minimal risk of toxicity a series of samples across the dosage interval may be used to estimate and undesirable side effects. However, this simple theory breaks down the area under the concentration-time curve (AUC). in a number of important respects, and the target range must always How often drugs should be monitored will also depend on the be considered as an adjunct to clinical judgment and not a substitute question to be answered and the clinical situation of the patient. Daily for it. For this reason, the term target range is preferred to the older monitoring may be necessary in critically ill patients with rapidly term therapeutic range. MONITORING DRUG THERAPEUTIC changing clearance, for example with aminoglycoside antibiotics. The optimum range of drug concentrations for a particular patient is a Dosage requirements for immunosuppressive drugs vary markedly in very individual matter, depending to some extent on the severity of the the early days and weeks posttransplantation, and frequent monitoring underlying disease process. This fact does not undermine the value is normally required. At the other end of the scale, stable patients on of TDM, but does require a clear understanding of why an individual long-term anticonvulsant or antidepressant therapy may need little or request has been ordered and how it can be interpreted in light of the no concentration monitoring in the absence of complications. patient’s condition. There is no reason to monitor drug concentrations Regular monitoring is useful (1) when optimizing dosage initially, in a patient who is clinically stable and not showing symptoms of (2) when other drugs are added to or subtracted from a regime to toxicity, except to establish a baseline in case any problems are guard against known or unexpected interactions, or (3) when renal subsequently encountered. or hepatic function is changing. Difficulties arise when, having made a measurement for no Correct interpretation and appropriate response particularly good reason on a stable patient, the clinician discovers that the result is outside the target range and feels compelled to do Even if a relevant question has been formulated, an appropriate something about it. In one of the earliest papers on TDM, Koch- specimen taken and an accurate result obtained, the whole exercise Weser6 wrote: “Therapeutic decisions should never be based solely is valueless unless the result is correctly interpreted and any on the drug concentration in the serum.” The cardinal principle, oft necessary action taken. Interpretation of drug concentrations repeated but still forgotten, is to treat the patient rather than the drug requires knowledge of the pharmacokinetic and pharmacodynamic concentration. factors affecting the drug in question, and may demand considerable expertise. Unfortunately, without effective educational programs, Drug concentrations above the target range do not invariably require users of TDM services frequently interpret results simply by a reduction in dosage. For immunosuppressants it may be necessary comparing them with the target range and then either do nothing or in some patients to run levels above the target range to avoid rejection react to bring the levels closer to the quoted range. Much harm can of a heart transplant. For other drugs it may be that if the patient is be done by this process, as it is frequently forgotten by clinicians or symptom-free, a careful search for signs of toxicity should be made. If laboratory workers, and the aim of the TDM process is to ameliorate no evidence is found, the patient may be best served by doing nothing.

13 14 BACK TABLE TO OF CONTENTS For some drugs (e.g., phenytoin), continued monitoring for the is to alter the dose interval rather than the dose amount (e.g., for development of long-term undesirable effects is advisable. Similarly, aminoglycosides),8 published nomograms are available to facilitate drug levels below the target range in a patient who is well and free dose adjustment. from symptoms do not require an increased dose,7 although in some Software exists to assist dosage prediction and ranges from automated cases (e.g., digoxin), they may provide evidence that the drug is no forms of simple pharmacokinetic equations to more sophisticated longer necessary and stopping it under medical supervision is systems that employ population pharmacokinetics, Bayesian statistical worth trying. theory, maximum likelihood estimations and neural networks. When serial serum concentrations are measured, it is possible to fit CALCULATION OF DOSAGE ADJUSTMENT pharmacokinetic models to the measured concentration versus time Drug concentration measurement in individual patients provides a data and estimate pharmacokinetic parameters for the individual surrogate endpoint for response, and may therefore be used to guide patient. A limitation of this approach is that it requires multiple blood MONITORING DRUG THERAPEUTIC dosage adjustment toward the optimal dose for a particular patient. samples, which is not always feasible or cost-effective for routine Several available approaches allow use of the serum concentration patient care. obtained on a known dosage regime to predict the new dosage regime. These approaches will deliver optimal drug concentrations and full An alternative approach is to use Bayesian principles for parameter details may be found in standard pharmacokinetic texts.5 estimation.9 In addition to measured serum concentrations, the Bayesian approach uses what is already known about a drug’s The most straightforward approach for drugs following first-order pharmacokinetic parameters in patients similar to the individual being (linear) pharmacokinetics is to use simple proportionality. A new evaluated (population pharmacokinetics). These a priori assumptions dose D can be calculated from the present dose D, the actual plasma N are then combined with one or more actual concentration-dose pairs concentration C and the desired plasma concentration C as follows: N to give a refined best estimate for the individual’s pharmacokinetic D parameters that can be used to predict future dose requirements. DN = x CN This approach forms the basis of many neural networks or other C computer programs for dosage optimization. Such systems have been described for a variety of drugs and in many cases made commercially For practical purposes, trough concentrations rather than steady-state available.10 They have undoubted value in experienced hands, concentrations are normally used. It must be recognized that when a particularly when complex drug regimes are involved. However, single dose/concentration data pair is being used in such calculations, care is needed in their use, particularly in the hands of people who great weight is being placed on a single measurement. There are a do not have a good understanding of the underlying principles and number of implicit assumptions, namely that (1) the correct dose was limitations. Software tools should be evaluated with regard to the given at the stated time, (2) an accurate measurement of the drug individual needs of hospitals and clinicians. The output from dosage concentration was made, (3) an accurate recording of the time of prediction software is only as good as the data fed into them, and dose sample collection was made, and (4) steady-state concentrations have predictions should always be checked by an experienced practitioner been achieved. Errors in any of these factors may result in erroneous before being used clinically. dosage predictions. For drugs that do not exhibit first-order kinetics (e.g., phenytoin), or where the response to inappropriate plasma concentrations

15 16 BACK TABLE TO OF CONTENTS OTHER APPROACHES TO OPTIMIZING THERAPY — Pharmacogenetic polymorphism is defined as the existence in a PHARMACOGENETICS AND BIOMARKERS population of two or more alleles (at the same locus) that result in We began this chapter by defining TDM as the use of drug or more than one phenotype with respect to the effect of a drug. The metabolite measurements in body fluids as an aid to monitoring term pharmacogenomics describes the range of genetic influences on therapy. In recent years, other methods of controlling drug therapy drug metabolism and its application to the practice of tailoring drugs have been introduced, and though they do not fit the strict definition and dosages to individual genotypes to enhance safety and/or efficacy. of TDM, they merit discussion as they are becoming increasingly This practice — often called “Personalized Medicine” — is a massive important. Pharmacodynamic monitoring is the study of the biological growth area for 21st century medicine. effect of a drug at its target site, and has been applied in the areas of Determination of an individual’s ability to metabolize a specific drug immunosuppressive therapy and cancer chemotherapy. For example, may be performed by either administering a test dose of the drug or the biological effect of the calcineurin inhibitor immunosuppressants a compound metabolized by the same enzyme system (phenotyping) MONITORING DRUG THERAPEUTIC (e.g., cyclosporine) can be assessed by measuring the reduced regulated or by specific genetic analysis (genotyping). The phenotyping and gene expression of nuclear factor of activated T cells (NFAT) regulator genotyping results can inform and improve the clinician’s ability genes. The main disadvantage of pharmacodynamic monitoring is the to adjust drug dosing according to the specific requirements of fact that the assays involved are often significantly more complex and the individual patient. For example, a number of enzymes of the time consuming than the measurement of a single molecular species cytochrome P450 superfamily show genetic polymorphisms that by chromatography or immunoassay. account for differences in clinical response. The CYP2D6 isoform Any biochemical measurement that can be used to determine efficacy, has well over 100 allelic variants and metabolizes a range of drugs extent of toxicity or individual pharmacodynamics for a therapeutic widely used in medicine, including many anti-arrhythmics and agent is termed a therapeutic biomarker. Biomarker monitoring antidepressants. CYP2D6 phenotypes may be divided into poor can provide an integrated measure of all biologically active species metabolizer (PM), extensive metabolizer (EM) and ultra-extensive (parent drug and metabolites), so target ranges can be defined more metabolizer (UEM) phenotypes (which have multiple copies of closely. In addition, biomarkers are often free from the matrix and the gene). Genetic analysis can define the CYP2D6 phenotype and drug disposition problems that bedevil TDM in some areas, notably identify the alleles associated with the PM phenotype (of which the immunosuppressants. most common are CYP2D6 *3, *4, *5, *6 and*7). Once determined, the phenotype or genotype can be used to guide dosing for any of the Pharmacogenetic studies (studies of hereditary influences, including drugs metabolized by the CYP2D6 isoform. However, there can be ethnicity, on pharmacological responses) have clear and wide- functional differences between genotype and phenotype. ranging clinical relevance. The enzymes that are responsible for metabolism of drugs and other compounds exhibit wide The clinical applications of pharmacogenomics are extensive. Some interindividual variation in their protein expression or catalytic examples are in anticoagulation (polymorphism of the CYP2C9 and activity, resulting in different drug metabolism phenotypes between VKORC1 genes), oncology (thiopurine methyltransferase isoforms individuals. This variation may arise from transient effects on the and the serum Her2/neu receptor), psychiatry (CYP2D6 isoforms), enzyme, such as inhibition or induction by other drugs, or may be epilepsy, pain control and other areas. at the gene level and result from specific mutations or deletions.

17 18 BACK TABLE TO OF CONTENTS The combination of classical TDM, pharmacodynamic biomarkers and considerable waste of analytical and financial resources, plus and pharmacogenetics will undoubtedly accelerate the development diminished standards of patient care and an understandable degree of and facilitate the clinical use of drugs, and will have a major role cynicism about the whole process. It is now abundantly clear that the in delivering therapeutic efficiency and improved patient outcome availability of accurate TDM data does not by itself improve symptom with less need for plasma concentration monitoring.12 However, control or reduce the incidence of toxicity. As long ago as 1985, in an integrating the information available from all three strands is a editorial on TDM, The Lancet18 noted that “If plasma drug assays complex challenge which requires sophisticated decision support are to be done, they must be accompanied by some form of education software and effective strategies for presenting the information in an system that tells the prescribing doctor the meaning of the result and accessible format to those responsible for patient care. In principle, what steps should now be taken.” This statement remains as true pretreatment pharmacogenetic profiling should allow identification of today as it was when it was written. individuals who are likely to be particularly susceptible or resistant to THERAPEUTIC DRUG MONITORING DRUG THERAPEUTIC a proposed treatment strategy, allowing better choice of starting dose or the use of a different drug. However, pharmacodynamic factors such as age, disease and other drugs mean that pharmacogenetics can never tell the whole story, hence the need for physiologically based pharmacokinetic models.13 Biomarkers of effect and drug or metabolite concentration measurements will still be needed to complete the picture and deliver truly personalized therapeutics.

EFFECTIVENESS OF TDM – DOES IT HELP PATIENTS? In an era of evidence-based medicine, the lack of early studies into the efficacy of TDM has undermined its informed use.14 The studies that accompanied the development and effective utilization of immuno- suppressants15 — and more recent studies on aminoglycosides16 and in epilepsy17 — have proved that properly applied TDM is effective and that the consequences of not performing adequate TDM for these classes of drugs are dire. The lesser impact in other areas of TDM16 emphasizes the need for clinical judgment for effective application, rather than uncritical ordering of tests. Requests made to TDM services are often inadequately thought out, badly executed or misinterpreted, and requesting clinicians are frequently unclear as to when TDM would be helpful, and reluctant to pay proper attention to the results once obtained. The consequences of this have been an increasing workload for analytical laboratories

19 20 BACK TABLE TO OF CONTENTS REFERENCES 1. Marks V. A historical introduction. In: Widdop B, ed. Ther Drug 10. Fuchs A, Csajka S, Thoma Y, et al. Benchmarking therapeutic drug Monit. Edinburgh: Churchill Livingstone; 1985:3-15. monitoring software: a review of available computer tools. Clin Pharmacokinet. 2013:52:9-22. 2. Buchthal F, Svensmark O, Schiller PJ. Clinical and electroencephalographic correlations with serum levels of 11. Bergan S, Bremer S, Vethe NT. Drug target molecules to guide diphenylhydantoin. Arch Neurol. 1960;2:624-631. immunosuppression. Clin Biochem. 2016;49:411-418. 3. Baastrup PC, Schou M. Lithium as a prophylactic agent. Arch Gen 12. Cremers S, Guha N, Shine B. Therapeutic drug monitoring in the Psychiatr. 1967;16:162-172. era of precision medicine: opportunities! Brit J Clin Pharmacol. 2016:82:900-902 4. Koch-Weser J. Serum drug concentrations in clinical perspective.

In: Richens A, Marks V, eds. Ther Drug Monit. Edinburgh: Churchill 13. Hartmanshenn C, Scherholz M, Androulakis IP. Physiologically- MONITORING DRUG THERAPEUTIC Livingstone; 1981:1-22. based pharmacokinetic models: approaches for enabling personalized medicine. J Pharmacokinet Pharmacodyn. 5. Rowland M, Tozer TN. Clinical Pharmacokinetics and 2016;43:481-504. Pharmacodynamics: Concepts and Applications. 4th ed. Philadelphia: Lippincott,Williams & Wilkins, 2010. 14. Schumacher GE, Barr JT. Total testing process applied to therapeutic drug monitoring: impact on patients’ outcomes and 6. Koch-Weser J. Drug therapy: serum drug concentrations as economics. Clin Chem. 1998;44:370-374. therapeutic guides. N Engl J Med. 1972;287:227-231. 15. Tsunoda SM, Aweeka FT. The use of therapeutic drug monitoring 7. Woo E, Chan YM, Yu YL, et al. If a well-stabilized epileptic to optimize immunosuppressive therapy. Clin Pharmacokinet. patient has a subtherapeutic antiepileptic drug level, should the 1996;30:107-140. dose be increased? A randomized prospective study. Epilepsia. 1988;29:129-139. 16. Touw DJ, Neef C, Thomson AH, Vinks AA. Cost-effectiveness of therapeutic drug monitoring: a systematic review. Ther Drug Monit. 8. Stankowicz MS, Ibrahim J, Brown DL. Once-daily aminoglycoside 2005;27:10-17. dosing: an update on current literature. Am J Health-System Pharm. 2015;72:1357-1364. 17. Rane CT, Dalvi SS, Gogtay NJ, et al. A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients 9. Lesko LJ, Schmidt S. Individualization of drug therapy: history, with generalized tonic-clonic epilepsy. Br J Clinical Pharmacol. present state and opportunities for the future. Clin Pharm Ther. 2001;52:193-195. 2012;92:458-466. 18. Editorial. What therapeutic drugs should be monitored? The Lancet. 1985;ii:309-310.

21 22 BACK TABLE TO OF CONTENTS WEBSITES DRUG DATA PROFILES The International Association of TDM and Clinical Toxicology: www.iatdmct.org PREFACE The following drug profiles contain data that have been compiled Cytochrome P450 drug interaction table from Indiana University from various reference sources and the clinical experience of the (Ed. David Flockhart): medicine.iupui.edu/clinpharm/ddis contributors.

Home Page of the Human Cytochrome P450 (CYP) Allele DRUG PROFILES DATA “Usual dosages” reflect those considered most likely to achieve Nomenclature Committee at Karolinska Institute: the desired serum concentrations in patients with normal renal www.cypalleles.ki.se and hepatic function. When variable dosages are recommended Talking glossary of genetic terms: National Human Genome Research for different patient groups, these have been represented Institute: www.genome.gov/glossary.cfm diagrammatically. Laboratory Medicine Practice Guidelines and Recommendations for Other parameters, such as the usual dosing interval, time to peak Laboratory Analysis and Application of Pharmacogenetics to Clinical concentration, time to steady-state serum concentration, elimination Practice. Edited by Roland Valdes, Jr., Deborah Payne, and Mark W. half-life and protein binding are described for patients with normal Linder. 2010: organ function and average pharmacokinetic characteristics. www.aacc.org/~/media/practice-guidelines/pharmacogenetics/pgx_ The target ranges quoted provide guidelines as to the drug guidelines.pdf concentrations, which are expected to achieve optimal therapeutic Personalized Medicine Coalition: effect in most patients. These target ranges are visualized as a green www.personalizedmedicinecoalition.org/ shaded area on the target range diagram lying between the sub- Paving the Way for Personalized Medicine; FDA’s role in a New Era of therapeutic (blue) concentration and the potentially toxic (red) drug Medical Product Development. 2013: concentration. www.fda.gov/downloads/ScienceResearch/SpecialTopics/ Only a partial list of toxic effects and factors affecting drug PersonalizedMedicine/UCM372421.pdf concentrations are provided. These lists are not intended to be Personalized Medicine in Europe: Enhancing Patient Access to comprehensive. For more detailed information on individual drug Pharmaceutical Drug-Diagnostic Companion Products. 2014: preparations and characteristics, the manufacturer’s package insert www.epemed.org/online/www/content2/104/107/910/ and the current medical literature should be consulted. pagecontent2/4339/791/ENG/EpemedWhitePaperNOV14.pdf The purpose of this manual is to assist clinicians in the exercise of FDA-CDRH’s Guidance for Pharmacogenetic Tests and Genetic Tests their independent professional judgment in the light of available for Heritable Markers, 2007: clinical information. Although the information contained in www.fda.gov/medicaldevices/deviceregulationandguidance/ this manual has been obtained from highly reputable sources guidancedocuments/ucm077862.htm and is believed to be accurate in accordance with currently available information, neither the authors, the editors nor Abbott

23 24 BACK TABLE TO OF CONTENTS Laboratories assume any liability in connection with the use of specific information contained herein. Complete information concerning clinical indications, dosages, mechanisms of action, modes and timing of elimination, and toxic effects of therapeutic drugs available from the drug manufacturer should always be consulted. DRUG PROFILES DATA

DRUG DATA PROFILES

ADDICTION THERAPEUTICS ANTIEPILEPTICS ANTINEOPLASTICS IMMUNOSUPPRESSIVE BUPRENORPHINE 29 CARBAMAZEPINE 55 BUSULFAN 99 AGENTS METHADONE 31 CLONAZEPAM 57 METHOTREXATE 101 CICLOSPORIN/CYCLOSPORINE 127 ESLICARBAZEPINE ACETATE 59 MYCOPHENOLATE 129 ETHOSUXIMIDE 61 SIROLIMUS 131 FELBAMATE 63 TACROLIMUS 133 ANALGESICS GABAPENTIN 65 ANTIRETROVIRALS ACETAMINOPHEN 35 LACOSAMIDE 67 ANTIRETROVIRALS 105 ACETYLSALICYLIC ACID 37 LAMOTRIGINE 69 MORPHINE 39 LEVETIRACETAM 71 PSYCHOACTIVE AGENTS OXCARBAZEPINE 73 TRICYCLIC ANTIDEPRESSANTS PHENOBARBITAL/PRIMIDONE 75 BRONCHODILATOR, AMITRIPTYLINE 137 PHENYTOIN/FOSPHENYTOIN 77 ANALEPTIC OTHERS PREGABALIN 79 ANTIBIOTICS THEOPHYLLINE 109 CLOZAPINE/OLANZAPINE 139 RUFINAMIDE 81 AMINOGLYCOSIDES CAFFEINE 111 FLUOXETINE 141 TIAGABINE 83 AMIKACIN 43 HALOPERIDOL 143 TOPIRAMATE 85 GENTAMICIN 45 LITHIUM 145 VALPROATE 87 TOBRAMYCIN 47 VIGABATRIN 89 CARDIAC AGENTS OTHER ANTIBIOTICS ZONISAMIDE 91 TEICOPLANIN 49 ANTI-ARRHYTHMICS VANCOMYCIN 51 AMIODARONE 115 DISOPYRAMIDE 117 ANTIFUNGALS FLECAINIDE 119 LIDOCAINE 121 POSOCONAZOLE/ VORICONAZOLE 95 CARDIAC GLYCOSIDES DIGOXIN 123

25 26 BACK TABLE TO OF CONTENTS ADDICTION THERAPEUTICS ADDICTION THERAPEUTICS

BUPRENORPHINE

METHADONE

27 28 BACK TABLE TO OF CONTENTS BUPRENORPHINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct treatment of opioid dependence • Analgesia Optimum sampling time Pre-dose (trough sample) Time to peak Depends on preparation used MODE OF ACTION • Partial μ opioid receptor agonist/antagonist Route of elimination Hepatic metabolism (<1% excreted renally)

USUAL DOSE AND DOSE INTERVAL Elimination half-life 24-44 hours (shorter in IV dosing) ADDICTION THERAPEUTICS • Opioid dependence: 0.8-4.0 mg daily sublingually, adjusted according Time to steady state ~10 days of chronic dosing to response to a maximum of 24 mg daily Protein binding ~96% • Analgesia: 0.2-0.4 mg every 6-8 hours; children age-dependent, confirm local practice Target range Threshold effect is said to be 0.7μ g/L (1.5 nmol/L) • Parenteral, for analgesia, and subdermal implant or transdermal patches are available for management of chronic opioid dependence

FACTORS AFFECTING CONCENTRATION • Twenty times more potent as an analgesic than morphine • Norbuprenorphine is the main metabolite by CYP3A4 • Hepatic failure reduces clearance TYPICAL ADULT DOSES (mg/d) • Norbuprenorphine metabolite is present in 20 times the concentration of buprenorphine in urine and is the target analyte

TOXIC EFFECTS • Buprenorphine has abuse potential, there is a risk of death; this may be 4.0 potentiated by other drugs; there appears to be a particular risk associated 4.0 with benzodiazepine use • Prolongs QT interval; interaction risk with other QT interval-prolonging 3.0 drugs (e.g., amitriptyline, amiodarone) — Withdrawal symptoms — GI disturbances 2.0 1.6 MONITORING THERAPY • Monitoring of plasma concentrations has been proposed but not yet widely applied 1.0 0.8 • Confirmation of the norbuprenorphine metabolite in urine is a check 0.6 on adherence 0 Opioid Analgesia Dependence

29 30 BACK TABLE TO OF CONTENTS METHADONE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct in treatment of opioid dependence Optimum sampling time Pre-dose (trough sample) • Severe pain Time to peak ~4 hours MODE OF ACTION Route of elimination Hepatic metabolism (~25% excreted renally) • Opiate μ receptor agonist: R-isomer (d) is 30 times more active than the S-isomer (l) Elimination half-life 15-40 hours (R-isomer ~37 hours, S-isomer ~28 hours) ADDICTION THERAPEUTICS USUAL DOSE AND DOSE INTERVAL • Opioid dependence: initially 10-40 mg daily as an oral solution, increasing by up Time to steady state 4-8 days of chronic dosing to 10 mg daily, but no more than 30 mg in a week, until no signs of withdrawal Protein binding ~90% (typically 60-120 mg daily) • Intravenous, intramuscular and subcutaneous routes also used Target range 150-250 μg/L (430-720 nmol/L) for opioid dependence • Analgesia: 5-10 mg every 6-8 hours, if for prolonged use twice daily

FACTORS AFFECTING CONCENTRATION • R-isomer effective analgesic • Enzyme-inducing drugs increase clearance • Urine pH affects excretion: acid faster clearance • Some anti-retrovirals (e.g., nelfinavir) increase clearance of both isomers TYPICAL ADULT DOSES (mg/d) • Mainly metabolized by CYP3A4 (minor: CYP2D6, CYP 2C9 and CYP1A2) 125 • R-isomer metabolized by CYP2C19 (EDDP) 120 • S-isomer metabolized by CYP2B6

TOXIC EFFECTS 100 • Tolerance develops, but is lost after cessation of dosing • Dose MUST be incremented, a standard dose to a naïve or an individual who has lost tolerance is potentially fatal 75 • Particular risk of fatality in children • Respiratory depression 50 • Vasodilation with hypotension 40

MONITORING THERAPY 25 • There is a threshold of serum concentrations above which to avoid withdrawal symptoms and a higher value above which side effects become undesirable 15 10 • No benefit in monitoring isomeric forms 0 • Routine practice in urine monitoring is to detect the EDDP (2-ethylidene-1,5- Opioid Analgesia dimethyl-3,3-diphenyl-pyrrolidine) metabolite as a marker of adherence Dependence to therapy

31 32 BACK TABLE TO OF CONTENTS ANALGESICS

ANALGESICS

ACETAMINOPHEN

ACETYLSALICYLIC ACID

MORPHINE

33 34 BACK TABLE TO OF CONTENTS ACETAMINOPHEN (PARACETAMOL)

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANALGESICS • Analgesic • Antipyretic Optimum sampling time Monitoring not necessary except in overdose (Samples >4 hours after overdose required for valid MODE OF ACTION interpretation) • Undefined — probably by inhibition of cyclooxygenase Time to peak 0.5-1.0 hour USUAL DOSE AND DOSE INTERVAL Route of elimination Hepatic metabolism (~3% excreted renally) • 500-1000 mg every 4-6 hours to a maximum of 4000 mg daily Elimination half-life 1-4 hours (shorter in children) • Child: age-dependent, conform to local practice Time to steady state 5-20 hours of chronic dosing FACTORS AFFECTING CONCENTRATION Protein binding 20-30% • Primarily cleared by conjugation in the liver; impaired hepatic function and, to a lesser extent, renal impairment may prolong half-life Target range Serum concentrations in overdose should be related to a hepatic damage nomogram in use locally TOXIC EFFECTS • Glutathione depletion through overdose, alcoholism, results in a toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) production causing potentially fatal hepatic damage; this may not be apparent for 3-6 days • Other side effects (e.g., rash) rare TYPICAL ADULT DOSES (g/d)

MONITORING THERAPY • There is no need to monitor therapy, measurements in overdose predict the probability of hepatotoxicity and guide the decision to administer antidote therapy; follow local protocols

4 4

1 0 Adults

35 36 BACK TABLE TO OF CONTENTS ACETYLSALICYLIC ACID (ASPIRIN)

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANALGESICS • Analgesic Optimum sampling time Pre-dose (trough sample) • Anti-inflammatory • Antiplatelet (prophylaxis of ischemic cerebrovascular disease and acute Time to peak 0.5-2.0 hours (preparation dependent) coronary syndromes) Route of elimination Hepatic metabolism (~10% excreted renally) MODE OF ACTION Elimination half-life Acetylsalicylic acid: 15 minutes; Salicylic acid: • Inhibition of cyclooxygenase 3 hours (single dose); ~20 hours (chronic dosing)

USUAL DOSE AND DOSE INTERVAL Time to steady state 5-7 days of chronic dosing • Analgesia/anti-inflammatory: 300-900 mg every 4-6 hours as necessary Protein binding ~50-90% (concentration dependent) to a maximum of 4000 mg daily Target range 150-300 mg/L (1.1-2.2 mmol/L) • Antiplatelet: 300 mg dispersed or chewed on presentation with a (anti-inflammatory, less for analgesia) myocardial ischemic event, then 50-100 mg daily as prophylaxis • Avoid use in children (risk of Reye’s syndrome)

FACTORS AFFECTING CONCENTRATION • pH-dependent gastric absorption • Metabolized to salicylic acid then to salicyl acyl glucuronide and other TYPICAL ADULT DOSES (mg/d) TARGET RANGE compounds (mg/L) (mmol/L) • Renal excretion pH dependent (more rapid at alkaline pH) 5000 • Hypoalbuminemia (decreased binding)

TOXIC EFFECTS 4000 4000 • Gastric irritation, contraindicated if previous ulcer • Increased bleeding times • Hypersensitivity reactions 3000 • Tinnitus, vertigo 300 2.2 • Bronchospasm 2000 • Hepatic and renal damage following overdose • HLA-DRB*1302-DQB1*0609-DPB*0201 associated with urticaria 150 1.1 1000 MONITORING THERAPY 900 • Now no longer advised as a nonsteroidal anti-inflammatory • Monitoring is only necessary in chronic anti-inflammatory dosing 0 0 0 • No need to monitor in low-dose therapy • Concentration measurements aid treatment in overdose

37 38 BACK TABLE TO OF CONTENTS MORPHINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANALGESICS • Acute pain relief (e.g., myocardial infarction) • Chronic pain relief in cancer Optimum sampling time Not established • May be used in management of opiate misuse Time to peak Depends on route of administration

MODE OF ACTION Route of elimination Hepatic metabolism (morphine); renal (M6G) • Morphine is a potent μ receptor-agonist; the 6-glucuronide metabolite has Elimination half-life 2 hours (morphine); 2-4 hours (M6G) more activity; morphine may be considered a prodrug Time to steady state 12-24 hours (morphine); 10-20 hours (M6G) USUAL DOSE AND DOSE INTERVAL Protein binding 35% (morphine); 15% (M6G) • Initially 10 mg (5 mg if elderly/frail) every 4 hours (by subcutaneous or IM injection), adjusted according to response; once pain is controlled, patients Target range Not established can be transferred to oral modified-release preparations • Maintenance dose: in palliative care, 100 mg every 12 hours is adequate in most patients, given as modified-release preparations; up to 600 mg every 12 hours may be required

TOXIC EFFECTS • Constipation, nausea and vomiting, dry mouth and drowsiness are common side effects TYPICAL ADULT DOSES (mg/d) • Addiction is a rare consequence in chronic analgesia 1250 • ABCC3 variants prolong respiratory depression 1200

MONITORING THERAPY • No evidence that concentration-led dosing is necessary 1000 • Wide range of plasma concentrations, dose interventions individualized to response 750 • Typical plasma morphine concentrations 2-500 nmol/L • Typical plasma M6G concentrations 25-5000 nmol/L 500

250

30 0

39 40 BACK TABLE TO OF CONTENTS ANTIBIOTICS

ANTIBIOTICS

AMINOGLYCOSIDES

AMIKACIN

GENTAMICIN

TOBRAMYCIN

OTHER ANTIBIOTICS

TEICOPLANIN

VANCOMYCIN

41 42 BACK TABLE TO OF CONTENTS AMIKACIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANTIBIOTICS • Broad spectrum antibiotic active against aerobic Gram-negative organisms including Pseudomonas aeruginosa and Mycobacteria Optimum sampling time Peak (only used on divided-dose regimes): 1 hour • Used in treatment of serious infections caused by gentamicin-resistant post-dose (30-60 minutes after infusion complete) Gram-negative bacilli as more resistant to enzyme inactivation Trough: immediately before next dose • Use is constrained by resistance and toxicity Time to peak 1 hour • Once-daily dosing limits toxicity and enhances efficacy Route of elimination >90% excreted renally MODE OF ACTION Elimination half-life 2-3 hours with normal renal function • Disruption of protein synthesis by irreversible binding to the 30S ribosomal subunit of susceptible organisms Time to steady state 10-15 hours with normal renal function Protein binding <10% USUAL DOSE AND DOSE INTERVAL • Once-daily dosing by intravenous infusion: initially 15 mg/kg (maximum 1.5 g), Target range Once-daily dosing: target is a trough concentration further dosing adjusted according to amikacin serum concentration of <5 mg/L, peak not necessary • By IM injection, slow IV injection or infusion: 15 mg/kg daily in two divided Multiple dosing: trough <10 mg/L, doses, increased to 22.5 mg/kg daily in three divided doses in severe infection; peak 20-30 mg/L maximum 1.5 g daily for up to 10 days • Child: 15 mg/kg daily in two divided doses (check local practice) • Dosing should generally not exceed 7 days

FACTORS AFFECTING CONCENTRATION • Large, highly polar molecule • Very poor oral bioavailability – must be given parenterally • Not metabolized, excreted renally • Short plasma half-life (2-3 hours) unless renal function impaired • Terminal half-life very long and drug may accumulate if therapy continued for >7-10 days

TOXIC EFFECTS • Vestibular and auditory damage (often irreversible) related to degree of exposure • Nephrotoxicity (reduces excretion and may precipitate vicious cycle) • May impair neuromuscular transmission – avoid in myasthenia gravis

MONITORING THERAPY • Trough concentration measurements in once-daily dosing, peak and trough measurements in multiple dose regimes; followed by appropriate dosage adjustment • Monitoring is essential to achieve effective therapy, especially in patients with renal impairment who are at particular risk

43 44 BACK TABLE TO OF CONTENTS GENTAMICIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANTIBIOTICS • Broad spectrum antibiotic active against aerobic Gram-negative organisms including Pseudomonas aeruginosa and some Gram-positive organisms such as Optimum sampling time Peak: 1 hour post-dose (30-60 minutes after Staphylococcus aureus infusion complete) • Used in treatment of serious infections sometimes with a penicillin or metronidazole (or both) Time to peak 1 hour • Use constrained by resistance and toxicity Route of elimination >90% excreted renally • Once-daily dosing limits toxicity and enhances efficacy • Used in combination with other antibiotics in endocarditis Elimination half-life 2-3 hours with normal renal function Time to steady state 10-15 hours with normal renal function MODE OF ACTION • Disruption of protein synthesis by irreversible binding to the 30S ribosomal subunit Protein binding <10% of susceptible organisms Target range Once-daily/extended dose regimes: USUAL DOSE AND DOSE INTERVAL Seek local advice for specific regime • By IM injection, slow IV injection or infusion Multiple-dose regimes: • Once-daily/extended dosing interval regimes Trough: <2 mg/L (<1 in endocarditis) • Once-daily 5-7 mg/kg, then adjust according to serum gentamicin concentration Peak: 5-10 mg/L (3-5 in endocarditis) • Multiple-dose regimes, 3-5 mg/kg daily (in divided doses every 8 hours) Child: 6 mg/kg daily (2 mg/kg every 8 hours) • Endocarditis (with other antibacterials) 1 mg/kg every 8 hours

TOXIC EFFECTS • Vestibular and auditory damage (often irreversible) • Nephrotoxicity (reduces excretion and may precipitate vicious cycle) • May impair neuromuscular transmission – avoid in myasthenia gravis

MONITORING THERAPY • Once-daily dosing regimes give higher peak and lower trough concentrations and have largely superseded multiple-dose regimes in patients with normal renal function • Guidance on concentration monitoring for these regimes should be sought locally • Multiple-dose regimes require peak and trough concentration measurements and appropriate dose adjustment • Monitoring is essential to achieve effective therapy, especially in patients with renal impairment who are at particular risk

45 46 BACK TABLE TO OF CONTENTS TOBRAMYCIN

KEY PHARMACOKINETIC PARAMETERS

CLINICAL USE ANTIBIOTICS • Broad spectrum antibiotic active against aerobic Gram-negative organisms including Pseudomonas aeruginosa and some Gram-positive organisms such as Optimum sampling time Peak: 1 hour post-dose (30-60 minutes after Staphylococcus aureus infusion complete) Trough: immediately before next dose • Used in treatment of serious infections sometimes with a penicillin or metronidazole (or both) Time to peak 1 hour • Slightly more active against Pseudomonas aeruginosa than gentamicin Route of elimination >90% excreted renally • Effective by nebulizer in chronic Pseudomonas aeruginosa infection in cystic fibrosis Elimination half-life 2-3 hours with normal renal function MODE OF ACTION Time to steady state 10-15 hours with normal renal function • Disruption of protein synthesis by irreversible binding to the 30S ribosomal subunit of susceptible organisms Protein binding <10% Target range Once-daily/extended-dose regimes: USUAL DOSE AND DOSE INTERVAL Seek local advice for specific regime • By IM injection, slow IV injection or infusion Multiple-dose regimes: • 3 mg/kg daily (in divided doses every 8 hours) Trough: <2 mg/L (<1 in endocarditis) Peak: 5-10 mg/L (3-5 in endocarditis) • Once-daily in severe infection up to 5 mg/kg daily in divided doses every 6-8 hours, reduced to 3 mg/kg daily as soon as clinically indicated • Child: 2.0-2.5 mg/kg every 8 hours • Endocarditis (with other antibacterials): 1 mg/kg every 8 hours

MONITORING THERAPY • Use of aminoglycosides is a delicate balance between achieving concentrations necessary for effect and avoiding toxicity • Monitoring is essential to achieve effective therapy, especially in patients with renal impairment who are at particular risk

47 48 BACK TABLE TO OF CONTENTS TEICOPLANIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANTIBIOTICS • Glycopeptide antibiotic with bactericidal activity against aerobic and anaerobic Gram-positive bacilli including multiresistant Staphylococci Optimum sampling time Trough: immediately before next dose (MRSA) Time to peak N/A • Used in prophylaxis and treatment of endocarditis and other serious infections caused by Gram-positive cocci Route of elimination 97% excreted renally • Also used (added to dialysis fluid) in treatment of dialysis-associated Elimination half-life 100-150 hours peritonitis (terminal) Very similar to vancomycin, but has a longer duration of action allowing • Time to steady state 14 days or more once-daily administration Protein binding >90% MODE OF ACTION • Inhibits cell wall synthesis in susceptible organisms Target range Trough: 15-60 mg/L (20-60 mg/L in endocarditis and for Staphylococcus aureus) USUAL DOSE AND DOSE INTERVAL • By intravenous injection or infusion: initially 400 mg minimum or 6 mg/kg, whichever is greater, every 12 hours for three doses; subsequently 400 mg or 6 mg/kg once daily (may be given by intramuscular injection) higher doses may be needed in severe infection Streptococcal or enterococcal endocarditis (with another antibiotic): TYPICAL ADULT DOSES (mg/kg/d) TARGET RANGE initially 10 mg/kg every 12 hours for three doses, then 10 mg/kg once daily 10 (mg/L) Child, by intravenous injection or infusion: initially 10 mg/kg every 10 12 hours for three doses, subsequently 6 mg/kg once daily (10 mg/kg once daily for severe infections or in neutropenia) 8 60 FACTORS AFFECTING CONCENTRATION • Large, highly polar molecule 6 • Very poor oral bioavailability – must be given parenterally 6 • Not metabolized, excreted renally • Long terminal half-life (>100 hours) 4 TOXIC EFFECTS • Neutropnia, thrombocytopenis 2 • Nephrotoxicity and ototoxicity rare, enhanced risk if used with an 15 aminoglycoside • Rashes, including toxic epidermal necrolysis 0 0 MONITORING THERAPY • Teicoplanin is not monitored routinely • Plasma concentrations may help to optimize therapy in some patients

49 50 BACK TABLE TO OF CONTENTS VANCOMYCIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS ANTIBIOTICS • Glycopeptide antibiotic with bactericidal activity against aerobic and anaerobic Gram-positive bacilli, including multiresistant Staphylococci Optimum sampling time Peak: 1 hour post-dose (30-60 minutes after (MRSA) infusion complete) • Used in prophylaxis and treatment of endocarditis and other serious Trough: immediately before next dose infections caused by Gram-positive cocci Time to peak 1 hour • May be used (added to dialysis fluid) in treatment of dialysis-associated Route of elimination 80% excreted renally peritonitis • Oral administration for Clostridium difficile infections Elimination half-life 4-7 hours with normal renal function (longer in the elderly) MODE OF ACTION Time to steady state 20-35 hours with normal renal function • Inhibits cell wall synthesis in susceptible organisms Protein binding <10% USUAL DOSE AND DOSE INTERVAL • By intravenous infusion: Target range Trough: 10-15 mg/L (15-20 mg/L for endocarditis) 1.0-1.5 g every 12 hours (over 65 years, 500 mg every 12 hours or Peak: 25-50 mg/L 1 g once daily) Child: 15 mg/kg every 8 hours, maximum 2 g daily

FACTORS AFFECTING CONCENTRATION TARGET RANGE • Large, highly polar molecule (mg/L) (mg/L) • Very poor oral bioavailability – must be given parenterally except in pseudomembranous colitis • Not metabolized, excreted renally • Short plasma half-life (4-6 hours) unless renal function impaired

TOXIC EFFECTS • Neutropenia, thrombocytopenia 50 • Nephrotoxicity and ototoxicity rare, enhanced risk if high doses or used with an aminoglycoside • Rashes including toxic epidermal necrolysis

MONITORING THERAPY 25 20 • Concentration monitoring required 10

0 0 Peak Trough

51 52 BACK TABLE TO OF CONTENTS TAB TITLE TAB ANTIEPILEPTICS

ANTIEPILEPTICS

CARBAMAZEPINE CLONAZEPAM ESLICARBAZEPINE ACETATE ETHOSUXIMIDE FELBAMATE GABAPENTIN LACOSAMIDE LAMOTRIGINE LEVETIRACETAM OXCARBAZEPINE PHENOBARBITAL/PRIMIDONE PHENYTOIN/FOSPHENYTOIN PREGABALIN RUFINAMIDE TIAGABINE TOPIRAMATE VALPROATE VIGABATRIN ZONISAMIDE

53 54 BACK TABLE TO OF CONTENTS CARBAMAZEPINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Partial and secondary generalized tonic-clonic seizures

• Primary generalized tonic-clonic seizures Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Prophylaxis of bipolar affective disorder, mania and as a mood stabilizer • Effective for pain relief in trigeminal neuralgia Time to peak 4-8 hours (longer with sustained-release forms)

MODE OF ACTION Route of elimination Hepatic metabolism (~3% excreted renally) • Probable blocking of use-dependent sodium channels, inhibiting repetitive firing Elimination half-life 10-20 hours (shorter in children or in patients on USUAL DOSE AND DOSE INTERVAL enzyme-inducing drugs) • Epilepsy: initially 100-200 mg 1-2 times daily, increasing to 0.8-1.2 g daily in divided Time to steady state 21-28 days after initiation until auto-induction is doses (lower doses in children also age-dependent, lower initial dose in elderly); up to 2 g may be needed complete; 2-6 days on chronic dosing • Prophylaxis of bipolar disorder: usually 400-600 mg daily in divided doses, Protein binding ~75% maximum 1.6 g daily • Trigeminal neuralgia: initially 100 mg 1-2 times daily, increasing to 200 mg 3-4 times Target range 4-12 mg/L (17-50 mmol/L) daily in divided doses, up to 1.6 g daily

FACTORS AFFECTING CONCENTRATION • Metabolized to the active epoxide by CYP3A4 • Minor metabolism by CYP2C8, diol formation by microsomal epoxide hydrolase • Liver disease reduces clearance TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Increased clearance in children and pregnancy, reduced in old age • Induces its own metabolism – half-life falls after 1-3 weeks’ administration (mg/L) (µmol/L) • Metabolism induced by phenytoin and phenobarbitone 2500 • Metabolism inhibited by valproate and lamotrigine

TOXIC EFFECTS 2000 2000 • Dose-limiting side effects: blurred vision, nystagmus, dizziness, ataxia, headache, nausea, vomiting 1600 • Erythematous rash in 3-5% of patients • Syndrome of inappropriate antidiuresis may occur (hyponatremia, water overload) 1500 • Cardiac conduction disorders (rarely) • Risk of Antiepileptic Hypersensitivity Syndrome • Patients need to be warned of the risk of blood, hepatic and skin disorders 1000 • HLA-B*1502 associated with Stevens-Johnson syndrome 12 50

MONITORING THERAPY 500 • Relationship between plasma concentration and effect complicated by active 400 4 17 metabolites (CBZ-epoxide); CBZ-epoxide measurement may be helpful in assessing adherence 200 • Some patients may be controlled at concentrations <4 mg/L or require concentrations 0 0 0 >12 mg/L Adults Adults (anticonvulsant) (anticon- (trigeminal- • Monitoring is essential when seizure control is difficult to attain, but some patients vulsant) neuralgia) can be managed effectively with minimal concentration monitoring • Blood count, renal and hepatic monitoring needed

55 56 BACK TABLE TO OF CONTENTS CLONAZEPAM

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • All forms of epilepsy, myoclonus Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS MODE OF ACTION • Potentiates the effects of GABA inhibition of the reticular pathways Time to peak ~1 hour Route of elimination Hepatic metabolism USUAL DOSE AND DOSE INTERVAL • 1 mg at night for four nights increasing according to response over Elimination half-life 19-50 hours 2-4 weeks to a maintenance dose of 4-8 mg Time to steady state 4-10 days FACTORS AFFECTING CONCENTRATION Protein binding ~85% • Metabolized by CYP 3A Target range 20-70 μg/L (63-222 nmol/L) • Protein binding ~85% • Extensive hepatic metabolism • Metabolites accumulate in renal failure

TOXIC EFFECTS • Drowsiness • Fatigue TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Respiratory depression (µg/L) (nmol/L) MONITORING THERAPY 10 • To confirm adherence • To confirm toxicity 8 8 70 222

2 20 63

1 0 0 0

57 58 BACK TABLE TO OF CONTENTS ESLICARBAZEPINE ACETATE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct therapy in adults with focal seizures with or without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS

MODE OF ACTION Time to peak 2-3 hours • Blocks voltage-gated sodium channels; exact mechanism unknown Route of elimination Mainly renal; some hepatic conjugation USUAL DOSE AND DOSE INTERVAL Elimination half-life 13-20 hours • 400 mg daily increasing after 1-2 weeks to 800 mg once daily Time to steady state 4-5 days (maximum 1200 mg) Protein binding ~30% FACTORS AFFECTING CONCENTRATION • Administered as the acetate, which is cleaved on first-pass metabolism to Target range As for 10-hydroxycarbazepine: 3-35 mg/L the active eslicarbazepine (12-140 μmol/L) • Renal clearance lower than glomerular filtration rate (GFR) suggesting tubular reabsorption • Reduce dose in renal impairment • S-enantiomer of the 10-hydroxy metabolite of oxcarbazepine • Minor active metabolites are R-licarbazepine and oxcarbazepine TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Metabolic clearance by glucuronidation (mg/L) (µmol/L) TOXIC EFFECTS 1000 • Syndrome of inappropriate antidiuresis: hyponatremia • Risk of Stevens-Johnson syndrome associated with HLA B*1502 800 800 • Prolonged PR interval

MONITORING THERAPY 600 • As for 10-hydroxycarbazepine, monitoring is rarely necessary

35 140 400 400

200

3 12 0 0 0

59 60 BACK TABLE TO OF CONTENTS ETHOSUXIMIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • First-line treatment for absence seizures • May be used in myoclonic seizures Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS Time to peak 2-4 hours (adults) 3-7 hours (children) MODE OF ACTION • Reduces the T-type calcium channels in primary afferent neurons Route of elimination Hepatic metabolism (20% excreted renally)

USUAL DOSE AND DOSE INTERVAL Elimination half-life 40-60 hours • Adults and children over six years: initially 500 mg daily, increased by Time to steady state 5-15 days of chronic dosing 250 mg at intervals of 4-7 days to usual dose of 1.0-1.5 g (maximum 2 g) daily Protein binding <5% • Child up to six years: initially 250 mg daily, increased gradually to usual dose of 20 mg/kg daily, maximum 1 g daily Target range 40-100 mg/L (280-710 μmol/L)

FACTORS AFFECTING CONCENTRATION • Metabolized by CYP3A4 to inactive hydroxyl metabolite • Low protein binding • Chiral drug, used clinically as racemate

TOXIC EFFECTS • Gastrointestinal – nausea, vomiting, anorexia TYPICAL ADULT DOSES (mg/d) TARGET RANGE • CNS – dizziness, lethargy, sedation (tolerance develops) (mg/L) (µmol/L) • Hiccup • Blood disorders (rarely) 2000 2000 MONITORING THERAPY • Monitoring rarely necessary • Long half-life requires slow dosage changes • Synergistic pharmacodynamic interaction with valproate in some cases 100 710 1000 1000

40 280

0 0 0

61 62 BACK TABLE TO OF CONTENTS FELBAMATE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunctive therapy for primary and partial tonic-clonic seizures • Used in Lennox-Gastaut syndrome Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS Time to peak 1-4 hours MODE OF ACTION • Blocks binding of glycine with glutamate to the N-methyl-D-aspartate Route of elimination 50% renal (NMDA) receptor Elimination half-life ~20 hours USUAL DOSE AND DOSE INTERVAL Time to steady state ~6 days of chronic dosing • 600-1200 mg (maximum 3600 mg) daily in 3-4 doses orally Protein binding ~25% FACTORS AFFECTING CONCENTRATION Target range 30-60 mg/L (126-252 μmol/L) • 50% excreted unchanged • Metabolized by CYP3A4 and CYP2E1 • Metabolites include 2-hydroxy, parahydroxy and the monocarbamate • Clearance increased by phenytoin and carbamazepine

TOXIC EFFECTS • Risk of serious toxicity: aplastic anemia and hepatic failure TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Atropaldehyde, a reactive metabolite, may cause aplastic anemia • Common side effects include anorexia, weight loss, vomiting, insomnia, (mg/L) (µmol/L) nausea, headache, dizziness and somnolence • Toxicity limits use to difficult-to-control epilepsy 1600 MONITORING THERAPY • Monitor liver function tests and full blood counts at least monthly 1200 • Felbamate increases phenytoin, phenobarbitone and valproate 1200 concentrations • Felbamate decreases carbamazepine concentrations 60 252 800

600 30 126 400

0 0 0

63 64 BACK TABLE TO OF CONTENTS GABAPENTIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Used in partial seizures with or without secondary generalization ANTIEPILEPTICS • Neuropathic pain Optimum sampling time Pre-dose (trough sample) • Trigeminal neuralgia Time to peak 2-3 hours

MODE OF ACTION Route of elimination Renal (100%) • Interaction with voltage-gated GABA channels resulting in GABA release Elimination half-life 5-7 hours

USUAL DOSE AND DOSE INTERVAL Time to steady state ~2 days of chronic dosing • Epilepsy: 100-300 mg three times daily; increase in 300 mg daily Protein binding <3% increments according to response to 3.6 g daily in three divided doses (maximum 4.8 g daily in three divided doses) Target range 2-20 mg/L (12-120 μmol/L) suggested

FACTORS AFFECTING CONCENTRATION • Renally excreted – accumulates in renal failure

TOXIC EFFECTS • Mild side effects (typically fatigue, somnolence, ataxia and dizziness) • Weight gain on chronic therapy • Avoid abrupt withdrawal TYPICAL ADULT DOSES (mg/d) TARGET RANGE

MONITORING THERAPY (mg/L) (µmol/L) 5000 4800 • Unnecessary

4000

3000 20 120 2000

1000

300 2 12 0 0 0

65 66 BACK TABLE TO OF CONTENTS LACOSAMIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct therapy for focal seizures with or without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS

MODE OF ACTION Time to peak 1-2 hours • Not known; may enhance slow inactivation of voltage-gated sodium Route of elimination Hepatic ~60%; some renal channels Elimination half-life ~13 hours USUAL DOSE AND DOSE INTERVAL Time to steady state 3-4 days • Orally: 50 mg twice daily, increased weekly by 50 mg twice daily; initial maintenance dose 100 mg twice daily (up to 200 mg twice daily) Protein binding ~15% • Also, oral loading dose regime under medical supervision of 200 mg, Target range 10-20 mg/L (40-80 μmol/L) then 12 hours later maintenance dose of 100 mg twice daily, increased weekly by 50 mg twice daily, depending on response to a maximum of 200 mg twice daily • Intravenous dosing options available under medical supervision

FACTORS AFFECTING CONCENTRATION • 100% bioavailability with or without food • Hepatic clearance via CYP3A4, CYP2c9, CYP 2C19 TYPICAL ADULT DOSES (mg/d) USUAL THERAPEUTIC RANGE • Liver disease decreases clearance (mg/L) (µmol/L) • Moderate increases in concentration in renal disease

TOXIC EFFECTS 400 • Cognitive disorder 400 • Drowsiness • Blurred vision 20 80 300 • Antiepileptic Hypersensitivity Syndrome (rarely)

MONITORING THERAPY 200 • Need for monitoring has not been established 200 10 40

100

0 0 0

67 68 BACK TABLE TO OF CONTENTS LAMOTRIGINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Effective first-line anticonvulsant

• Partial and generalized tonic-clonic seizures Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Use alone or in combination with other anticonvulsants Time to peak ~3 hours • Also used in treatment of bipolar disorder in some countries Route of elimination Hepatic metabolism (~10% excreted renally) MODE OF ACTION Elimination half-life 20-35 hours (shorter in children); approximately Blocks the slow-inactivated sodium channels inhibiting glutamate and • 15 hours when given with enzyme inducers; aspartate release approximately 60 hours when given with valproate USUAL DOSE AND DOSE INTERVAL Time to steady state 5-7 days of chronic dosing • Monotherapy: 25 mg once daily for two weeks, then 50 mg once daily for two weeks, then increase by up to 100 mg once daily to normal maintenance dose Protein binding ~60% of 100-200 mg (maximum 500 mg) daily in one or two divided doses Target range 3-15 mg/L (12-59 μmol/L) • Adjunctive therapy with valproate: half dosing rate for monotherapy; with enzyme (see Monitoring Therapy) inducers: double monotherapy dosing rates to a maximum of 400 mg per day • Adjunctive therapy without valproate or enzyme inducers: as for monotherapy; check local practice

FACTORS AFFECTING CONCENTRATION • Phenytoin, carbamazepine and phenobarbitone induce metabolism TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Valproate significantly decreases clearance (mg/L) (µmol/L) • Lamotrigine inhibits carbamazepine epoxide formation •Metabolized by hepatic glucuronidation • Clearance increased in the first trimester of pregnancy and in patients on oral contraception 400

TOXIC EFFECTS • Life-threatening skin reactions such as Stevens-Johnson syndrome and toxic 300 15 59 epidermal necrolysis may occur, usually within the first 8 weeks; may be associated with Antiepileptic Hypersensitivity Syndrome; combination with valproate increases the risk 200 200 • Neurological side-effects (e.g., weakness, visual disturbance, dizziness) • Gastrointestinal disturbances 100 MONITORING THERAPY 100 • Plasma concentration reflects effect 3 12 • Target range: 3-15 mg/L (12-59 μmol/L) when used as single therapy 0 • Toxicity occurs in 5% above 15 mg/L (59 μmol/L), rising to 15% above 0 0 20 mg/L (78 μmol/L) • Interactions with other anticonvulsants mean measurement of concentrations is helpful in designing a dosing regime

69 70 BACK TABLE TO OF CONTENTS LEVETIRACETAM

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Monotherapy or adjunctive therapy of focal seizures with or without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS

MODE OF ACTION Time to peak 0.5-1.0 hour • Binds to synaptic vesicle protein 2A; precise mechanism of action Route of elimination Renal elimination of ~65% unchanged drug unknown. Elimination half-life 6-8 hours DOSE AND DOSE INTERVAL Time to steady state ~2 days of chronic dosing • Adult doses (check local guidance for children) • Monotherapy: initially 250 mg once daily, increased to 250 mg twice daily Protein binding <10% after one to two weeks; thereafter increased in 250 mg twice daily steps Target range 12-46 mg/L (70-268 μmol/L) according to response to a maximum of 1.5 g twice daily • Adjunctive therapy: 250 mg twice daily initially, increased by 500 mg twice daily every 2-4 weeks to a maximum of 1.5 g twice daily

FACTORS AFFECTING CONCENTRATION • Approximately 65% excreted renally as unchanged drug • Approximately 25% excreted renally following hydroxylation of the acetamide group TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Not metabolized by cytochrome enzymes, so not induced or inhibited by (mg/L) (µmol/L) drugs metabolized by these enzymes • Renal excretion means decreased clearance when renal function impaired • Analogue of brivaracetam 46 268 4000 TOXIC EFFECTS • Good safety profile 3000 3000 • Principal side effects are asthenia, dizziness and somnolence • Wide range of more severe side effects occur rarely

MONITORING THERAPY 2000 • No evidence to justify routine monitoring • Target range of 12-46 mg/L (70-268 μmol/L) has been suggested 1000 12 70

500 0 0 0

71 72 BACK TABLE TO OF CONTENTS OXCARBAZEPINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Monotherapy and adjunctive therapy of partial seizures with or without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Pain relief in trigeminal neuralgia Time to peak 1-3 hours (10-OHC 4-6 hours) MODE OF ACTION Route of elimination Hepatic metabolism (conversion to 10-OHC • A prodrug, reduced to the active 10-hydroxy carbamazepine (10-OHC), followed by glucuronidation, minor metabolism to blocking sodium channels and inhibiting neuronal firing the diol); about 20% excreted unchanged in urine

USUAL DOSE AND DOSE INTERVAL Elimination half-life ~2 hours (10-OHC 7-13 hours) • 300 mg twice daily initially, increasing in steps of up to 600 mg daily at Time to steady state 2-7 days of chronic dosing for 10-OHC weekly intervals Protein binding ~60% (~40% for 10-OHC) • Typical doses 600-2400 mg daily in divided doses • Children 6-18 years: initially 8-10 mg/kg daily, increasing weekly by similar Target range 3-35 mg/L (12-140 μmol/L) for 10-OHC doses to a maximum of 46 mg/kg in divided doses • Trigeminal neuralgia: dosing as above

FACTORS AFFECTING CONCENTRATION • Prodrug for the 10-hydroxy metabolite (10-OHC) by cytosolic arylketone TYPICAL ADULT DOSES (mg/d) TARGET RANGE FOR THE reductase 10-HYDROXY METABOLITE • Minimal cytochrome enzyme metabolism of 10-OHC means that inductive/ (mg/L) (µmol/L) inhibitory drugs do not affect its pharmacokinetics • High-fat or high-protein meals increase oxcarbazepine bioavailability by 35 140 about 20% 2400 2400 • Enantiomeric: 10-OHC R-isomer has slower elimination • 10-OHC cleared by conjugation 1800 TOXIC EFFECTS • Similar neurological side-effect profile to carbamazepine • High incidence (~25%) of hyponatremia (<125 mmol/L) 1200 • Patients need to be warned of the risk of blood, hepatic and skin disorders • Risk of Stevens-Johnson syndrome associated with HLA B*1502 600 600 MONITORING THERAPY 3 12 • Monitoring of oxcarbazepine is unnecessary 0 • A target range for 10-OHC of 3-35 mg/L (12-140 μmol/L) has been used, 0 0 though monitoring is rarely required

73 74 BACK TABLE TO OF CONTENTS PHENOBARBITAL/PRIMIDONE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS (PHENOBARBITAL) • All forms of epilepsy except absence seizures ANTIEPILEPTICS • Phenobarbital used as second-line treatment in status epilepticus Optimum sampling time Not important at steady state (as long as half-life and dosage frequency causes minimal concentration • Primidone is a prodrug for phenobarbital; it is rarely used variation between doses) • Previously widely used, phenobarbital is now used infrequently Time to peak 0.5-4.0 hours (see Optimum sampling time above) MODE OF ACTION Route of elimination ~70% hepatic metabolism (~30% excreted renally) • Enhances the effect of GABA by opening the chloride channel at the GABA receptor Elimination half-life 80-120 hours (shorter following metabolic induction) USUAL DOSE AND DOSE INTERVAL Time to steady state 17-25 days of chronic dosing; however, metabolic • Phenobarbital: 60-180 mg at night; 5-8 mg/kg for children induction will require dose changes and the • Primidone: 125 mg at night, increasing by 125 mg every three days to establishment of a new steady state 500 mg in two divided doses; increase by increments of 250 mg every three days to a maintenance dose of 750-1500 mg daily in two divided doses Protein binding ~50% Target range 10-40 mg/L (40-160 μmol/L) FACTORS AFFECTING CONCENTRATION • Phenobarbital induces its own metabolism • Phenytoin and valproate decrease clearance TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Renal impairment decreases clearance Phenobarbital Primidone (mg/L) (µmol/L) • Renal excretion is pH sensitive, alkalinity increases clearance 250 1500 1500 • CYP2C9 and CYP2C19

TOXIC EFFECTS 200 1200 • Sedation is a common early side effect, tolerance develops 180 • Hyperkinesia and behavioral disturbances in children 150 • Nystagmus and ataxia 900 40 160

• Megaloblastic anemia (1-2%) 750 • Osteomalacia 100 600 • Avoid in porphyria • Rash occurs in 1-2% of patients 50 60 300 MONITORING THERAPY 10 40 • Tolerance occurs • Poor correlation between drug concentration and effect 0 0 0 0 Adult • Target range must be interpreted flexibly • Very low phenobarbital concentrations may have a significant anticonvulsant effect and withdrawal may provoke breakthrough seizures

75 76 BACK TABLE TO OF CONTENTS PHENYTOIN/FOSPHENYTOIN

CLINICAL USE • Widely used alone and in combination with other anticonvulsants • All forms of epilepsy except absence seizures KEY PHARMACOKINETIC PARAMETERS • Prophylaxis in neurosurgery or severe head injury ANTIEPILEPTICS • Fosphenytoin, a phenytoin prodrug, for IV use in status epilepticus Optimum sampling time In steady state this is not too important as the • Used to treat trigeminal neuralgia if carbamazepine inappropriate effective half-life is long, a trough sample if on MODE OF ACTION short-term fosphenytoin • Limits spread of seizure activity through effects on the sodium channel of neuronal wall membranes Time to peak 3-12 hours (dose and formulation dependent)

USUAL DOSE AND DOSE INTERVAL Route of elimination Hepatic metabolism (>95%) • 150-300 mg per day initially, adjust according to response and plasma concentration, Apparent elimination 6-24 hours (up to 60 hours if metabolism saturated) usual dose 200-500 mg daily half-life • Child: initially 5 mg/kg in two divided doses to typically 4-8 mg/kg (maximum 300 mg) • Fosphenytoin is equivalent to phenytoin in a weight ratio of 3:2; doses are stated in Time to steady state 2-6 days of chronic dosing phenytoin equivalents (PE) (e.g., 1.5 mg fosphenytoin = 1.0 mg PE) • Fosphenytoin (status epilepticus): 20 mg (PE)/kg initially, then 50-100 mg (PE)/minute; Protein binding ~92% maintenance 4-5 mg (PE)/kg daily in 1 or 2 divided doses with trough plasma concentration monitoring; consult local guidance for children Target range Total phenytoin: 5-20 mg/L (20-80 μmol/L) Free phenytoin: 0.5-2.0 mg/L (2-8 μmol/L) FACTORS AFFECTING CONCENTRATION Vmax: 100-1000 mg daily (variable in children) • Metabolized by CYP2C9 (90%) and 2C19 (10%), limited capacity Km: 1-15 mg/L (4-60 μmol/L) (variable in children) • Saturation kinetics (nonlinear or zero-order kinetics) – i.e., small changes in dose may lead to disproportionate changes in plasma phenytoin concentrations • Individuals vary as to when their kinetics become nonlinear • Valproate displaces protein-bound phenytoin TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Variable and slow absorption rate (TOTAL PHENYTOIN) (mg/L) (µmol/L) • Unbound (i.e., free phenytoin) concentrations affected by some drugs or changes in 500 availability of albumin for binding 500 • Pregnancy increases clearance • Induces metabolism of some other antiepileptics and many other drugs • Bioavailability variable between different formulations 400 TOXIC EFFECTS • Poor side-effect profile limits use 300 • Neurotoxicity (nystagmus, dysarthria, diplopia, ataxia) • Chronic side effects may be disabling or disfiguring (e.g., ataxia or gingival hyperplasia, 20 80 acne and hirsutism) • Risk of Antiepileptic Hypersensitivity Syndrome 200 • Rare severe reactions (e.g., megaloblastic anemia) • Paradoxical seizures if dose too high 150 5 20 100 MONITORING THERAPY • Essential to monitor therapy to enable informed and safe-dosage changes • There is no dose-effect relationship • Saliva concentrations reflect plasma concentrations 0 0 0 Free plasma concentrations best reflect effect Adults, children, • infants > 30 months • Dose changes should be made judiciously • Be aware of drug interactions

77 78 BACK TABLE TO OF CONTENTS PREGABALIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct therapy for focal seizures with or without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Generalized anxiety disorder Time to peak ~1.5 hours • Peripheral and central neuropathic pain Route of elimination >95% renal MODE OF ACTION Elimination half-life ~6 hours • Not fully determined; GABA structural analog: actions include increases in neuronal GABA levels and binding to the alpha2-delta site (an auxiliary Time to steady state 1-2 days subunit of voltage-gated calcium channels) Protein binding 0% USUAL DOSE AND DOSE INTERVAL Target range 2-5 mg/L (13-31 μmol/L) • Adjunct therapy: initially 25 mg twice daily, increasing in weekly steps of 50 mg daily to 300 mg daily in 2-3 divided doses (maximum 600 mg) • Neuropathic pain and anxiety disorder: 150 mg daily in 2-3 divided doses, increasing in 3-7 days to 300 mg daily in 2-3 divided doses (maximum 600 mg)

FACTORS AFFECTING CONCENTRATION • Not metabolized TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Renally excreted - renal impairment decreases clearance (mg/L) (µmol/L) 500 • Not protein bound

TOXIC EFFECTS • Visual disturbances 400 • Muscle and movement disorders • Panic attacks 300 300 MONITORING THERAPY 5 31 • Need for monitoring has not been established 200 • Toxicity more likely at concentrations above 10 mg/L

100 2 13

50 0 0 0

79 80 BACK TABLE TO OF CONTENTS RUFINAMIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct therapy in Lennox-Gastaut syndrome • Tertiary specialist use in refractory tonic or atonic seizures Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS Time to peak 4-6 hours MODE OF ACTION • Not elucidated — prolongs inactive state of voltage-gated sodium channel, Route of elimination Hepatic metabolism limiting neuronal firing Elimination half-life 6-10 hours USUAL DOSE AND DOSE INTERVAL Time to steady state 2-3 days • 200 mg twice daily initially; increase in 200 mg steps no earlier than two days according to response; maximum doses are weight-dependent Protein binding ~30% (30-50 kg: 900 mg twice daily; 50-70 kg: 1200 mg twice daily; >70 kg: 1600 mg Target range 3-30 mg/L (13-126 μmol/L) twice daily)

FACTORS AFFECTING CONCENTRATION • Extensive hepatic metabolism to a carboxylic metabolite by amidase hydrolysis • No CYP metabolism, but may be a weak inducer of CYP3A4 • Food increases bioavailability • Nonlinear pharmacokinetics TYPICAL ADULT DOSES (mg/d) TENTATIVE TARGET RANGE • Valproate inhibits clearance by ~50% (µg/L) (nmol/L) 4000 TOXIC EFFECTS • Rash 3200 • Risk of Antiepileptic Hypersensitivity Syndrome 3000 • Nausea and other abdominal disturbances • Fatigue 30 126 • Tremor 2000 MONITORING THERAPY • Need for monitoring has not been established • Nonlinear pharmacokinetics suggest concentration monitoring may 1000 be appropriate

400 3 13 0 0 0

81 82 BACK TABLE TO OF CONTENTS TIAGABINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Adjunct therapy where other antiepileptics have been unsatisfactory for focal seizures with and without secondary generalization Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS

MODE OF ACTION Time to peak 45 minutes • Inhibits neuronal and glial uptake of GABA Route of elimination Hepatic metabolism USUAL DOSE AND DOSE INTERVAL Elimination half-life 7-9 hours • 5-10 mg daily, increasing by 5-10 mg daily at weekly intervals to 30-45 mg Time to steady state ~2 days daily in 2-3 divided doses, if given with enzyme-inducing drugs or 15-30 mg daily without enzyme-inducing drugs Protein binding 96%

FACTORS AFFECTING CONCENTRATION Target range 20-100 μg/L (50-250 nmol/L) • Highly protein-bound • Hepatic clearance: CYP3A4 • Enzyme-inducing drugs increase clearance by ~60%

TOXIC EFFECTS • Avoid in porphyria • Tremor TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Psychosis (µg/L) (nmol/L) 60 • Emotional lability

MONITORING THERAPY • Need for monitoring has not been established 100 250 45 45

15 15 20 50

0 0 0

83 84 BACK TABLE TO OF CONTENTS TOPIRAMATE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Monotherapy or adjunctive therapy for generalized, tonic-clonic or partial seizures Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Adjunctive therapy for seizures in Lennox-Gastaut syndrome Time to peak 1.0-2.5 hours • Migraine prophylaxis Route of elimination ~90% excreted renally MODE OF ACTION Elimination half-life 20-30 hours • Uncertain; reduces number of action potentials and may block sodium voltage channels Time to steady state 5-7 days of chronic dosing Protein binding ~15% USUAL DOSE AND DOSE INTERVAL • Monotherapy: 25 mg at night for a week, then increments of 25-50 mg daily Target range 5-20 mg/L (15-60 μmol/L) in two divided doses at intervals of 1-2 weeks; usual dose 100-200 mg daily in two divided doses, maximum of 500 mg daily Child over 6 years: 0.5-1.0 mg/kg at night initially, increasing by 0.5-1.0 mg/kg daily at intervals of 1-2 weeks to a maximum of 15 mg/kg daily in two divided doses (maximum 500 mg) • Adjunctive therapy: as for monotherapy, but a maximum dose of 400 mg daily Child: 25 mg at night for one week incrementing by 1-3 mg/kg daily TYPICAL ADULT DOSES (mg/d) TARGET RANGE over 1-2 weeks in two divided doses to a maximum of 15 mg/kg daily (maximum 400 mg) (mg/L) (µmol/L)

FACTORS AFFECTING CONCENTRATION • Excreted renally – clearance reduced in renal impairment 800 • Increased clearance if given with carbamazepine or felbamate

TOXIC EFFECTS 600 • Risk of acute myopia with secondary angle-closure glaucoma, typically within a month of starting therapy; raised intraocular pressure (monitor) 500 20 60 • Need adequate hydration to avoid nephrolithiasis as makes urine alkaline 400 favoring calcium phosphate stones • Avoid in porphyria 200 MONITORING THERAPY • Side effects worsen above 25 mg/L 5 15 25 • Usefulness of monitoring has not been established 0 0 0 Epilepsy

85 86 BACK TABLE TO OF CONTENTS VALPROATE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • All forms of epilepsy

• Primary generalized epilepsy; drug of choice in generalized absences, myoclonic, Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS tonic-clonic, focal atonic and tonic seizures • Acute mania associated with bipolar disorder Time to peak 1-4 hours (longer with enteric-coated forms: • Migraine prophylaxis 3-8 hours)

MODE OF ACTION Route of elimination ~95% hepatic metabolism • Several possible mechanisms including increased GABA turnover and limiting Elimination half-life 9-16 hours (monotherapy) of voltage dependent sodium channels. Time to steady state 3-7 days of chronic dosing USUAL DOSE AND DOSE INTERVAL • 600 mg daily in two doses after food, increasing by 200 mg daily every three days to Protein binding ~95% (concentration dependent, decreasing a maximum of 2500 mg daily; usual dose 1000-2000 mg daily binding above ~80 mg/L [320 μmol/L]; also affected • Child under 12 years: 10-15 mg/kg initially (maximum 600 mg) daily in one or two by endogenous metabolites) divided doses, usual maintenance dose 25-30 mg/kg daily in two divided doses • Mania (as semisodium valproate [Depakote]): initially 750 mg daily in 2-3 divided Target range There is little evidence for the 50-100 mg/L doses increased according to response; usual dose as above (350-700 μmol/L) range often cited, or the range • Migraine prophylaxis: initially 200 mg twice daily, increased if necessary to of 50-125 mg/L (350-870 μmol/L) cited for bipolar 1200-1500 mg daily in divided doses disorder monitoring; plasma concentrations show poor correlation with effect FACTORS AFFECTING CONCENTRATION • Saturable protein binding results in dose-dependent free-fraction increases, hence variability across the dosage interval • Clearance increased by carbamazepine, phenytoin and phenobarbital TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Clearance depends on free fraction and influenced by displacement by endogenous metabolites (e.g., free fatty acids, affected by hypoalbuminemia) (mg/L) (µmol/L) • Non-linear total valproic acid kinetics, but free valproic acid kinetics are linear 2500

TOXIC EFFECTS • Hepatotoxicity, including hepatic failure, usually in first 6 months; higher risk 2000 2000 in children <3 years and on multiple anticonvulsant therapy; 4-ene metabolite is hepatotoxic; isolated transaminase rises are usually transient, but discontinue therapy if prothrombin time prolonged • Pancreatitis 1500 • Weight gain common 100 700 • Nausea, vomiting (reduced with enteric-coated forms) 1000 • Teratogenic (association with open spina bifida) 1000 • Hyperammonemia • Thrombocytopenia 50 350 500 MONITORING THERAPY • Monitor full blood count and liver function • The evidence is AGAINST monitoring plasma concentrations in epileptic or bipolar 0 disorder patients as there is wide intraindividual variation in concentrations with no 0 0 relationship to therapeutic effect; toxicity may be related to longer half-life metabolites

87 88 BACK TABLE TO OF CONTENTS VIGABATRIN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Specialist-initiated adjunctive therapy where other anticonvulsants have failed Optimum sampling time Pre-dose (trough sample) ANTIEPILEPTICS • Monotherapy for infantile spasms (West’s syndrome) Time to peak 0.5-2.0 hours MODE OF ACTION Route of elimination ~70% excreted renally • GABA transaminase inhibitor, raising GABA availability Elimination half-life 6-8 hours — S(+), active isomer elimination age USUAL DOSE AND DOSE INTERVAL independent, the R(-) inactive isomer clearance increases as children mature • 1000 mg initially, increased by 500 mg increments at weekly intervals to a maximum of 3000 mg daily in one or two divided doses Time to steady state 4 days of chronic dosing (clinical effects of changing Children: seek local advice dose take 2-10 days to be fully manifest) • Infantile spasms: 15-25 mg/kg initially twice daily; adjust according to Protein binding ~0% response over a week up to 150 mg/kg daily Target range No evidence for monitoring FACTORS AFFECTING CONCENTRATION • Supplied as a racemate, though only the S(+) isomer has pharmacological activity • No significant protein binding • Excreted renally – clearance reduced in renal impairment TYPICAL ADULT DOSES (mg/d)

TOXIC EFFECTS • Irreversible visual-field defects • Neurological (e.g., drowsiness, stupor, impaired concentration, slow-wave EEG) 4000

MONITORING THERAPY • Irreversible enzyme inhibitor – long pharmacodynamic half-life 3000 3000 • There is no evidence to support routine plasma concentration monitoring

2000

1000 1000

89 90 BACK TABLE TO OF CONTENTS ZONISAMIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Focal seizures with or without secondary generalization • Adjunctive therapy for refractory focal seizures Optimum sampling time Long half-life makes sampling time less critical ANTIEPILEPTICS in steady state (however, sampling at trough is MODE OF ACTION advised) • Several modes of action including voltage-gated sodium channel and T-type Time to peak <2 hours calcium channel blocking, inhibition of neurotransmitter release Route of elimination ~70% hepatic metabolism (remainder excreted USUAL DOSE AND DOSE INTERVAL renally) • Monotherapy: 100 mg once daily for two weeks, increased by 100 mg at two Elimination half-life ~65 hours (50% less if taken with enzyme-inducing week intervals to 300 mg daily (maximum 500 mg daily) drugs); half-life in red blood cells ~105 hours • Adjunct therapy: 50 mg daily in two divided doses increasing weekly thereafter as required by 100 mg daily in two divided doses to a maximum Time to steady state ~2 weeks of chronic dosing of 500 mg daily in two divided doses Protein binding ~40% FACTORS AFFECTING CONCENTRATION Target range 10-40 mg/L (47-188 μmol/L) • Metabolized by N-acetyltransferase-2 (NAT-2) and by CYP3A4. • Clearance increased by enzyme-inducing drugs • Lamotrigine may inhibit clearance TYPICAL ADULT DOSES (mg/d) USUAL THERAPEUTIC • Saturable binding of zonisamide to red cells (maximized before RANGE therapeutically effective concentrations are reached) (mg/L) (µmol/L)

TOXIC EFFECTS • Sensitivity to sulfonamides (zonisamide is a sulfonamide derivative) • Nephrolithiasis (incidence ~1%) 800 • Hyperthermia • Metabolic acidosis 600 40 188 •Weight loss 500

MONITORING THERAPY 400 • Evidence for toxicity being associated with concentrations over 40 mg/L (190 μmol/L) • Interaction with other anticonvulsants and the long half-life make 200 10 47 monitoring helpful in deciding dosing

0 50 0 0

91 92 BACK TABLE TO OF CONTENTS TAB TITLE TAB ANTIFUNGALS

ANTIFUNGALS

POSOCONAZOLE/VORICONAZOLE

93 94 BACK TABLE TO OF CONTENTS POSOCONAZOLE/VORICONAZOLE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS

• Systemic treatment of common fungal infections ANTIFUNGALS • Posoconazole has the broadest spectrum of activity Optimum sampling time Pre-dose (trough sample) • Voriconazole lacks activity against mucoraceous molds Time to peak Varies with drug and route of administration

MODE OF ACTION Route of elimination Hepatic metabolism • Inhibit ergosterol production by binding and inhibiting Elimination half-life Posoconazole: 25-35 hours; lanosterol-14alpha-demethylase Voriconazole: ~6 hours (dose-dependent)

USUAL DOSE AND DOSE INTERVAL Time to steady state 7 days (posoconazole) • Posoconazole: 800 mg daily in 2-4 divided doses (prophylaxis of invasive Protein binding Posoconazole: >98%; Voriconazole 58% fungal infections in immunocompromised patients: 600 mg daily in three divided doses) Target range Posoconazole: trough concentrations above • Voriconazole, by mouth (patients >40 kg): 400 mg twice daily for 1.0 mg/L (1.4 μmol/L) (0.7 mg/L [1.0 μmol/L] two doses, then 200 mg twice daily increasing to 300 mg twice daily for prophylaxis) if clinically indicated Voriconazole: trough concentration above IV: 6mg/kg every 12 hours for two doses, then 4 mg/kg every 12 hours 1.0 mg/L (3 μmol/L) and below 5.0-6.0 mg/L (15-17 μmol/L) FACTORS AFFECTING CONCENTRATION • Posconazole: variable absorption from the gut • Voriconazole: polymorphism in the CYP 2C19 isoenzyme

TOXIC EFFECTS • Posoconazole: nausea, vomiting, hepatotoxicity • Voriconazole: liver dysfunction, visual disturbances, skin reactions, neurotoxicity (confusion)

MONITORING THERAPY • Posoconazole: monitoring recommended for prophylaxis and treatment monitoring; measure in first week and regularly thereafter • Voriconazole: monitoring recommended for treatment monitoring and assessment of toxicity; measure in the first 5 days of therapy and regularly thereafter

95 96 BACK TABLE TO OF CONTENTS TAB TITLE TAB ANTINEOPLASTICS

ANTINEOPLASTICS

BUSULFAN

METHOTREXATE

97 98 BACK TABLE TO OF CONTENTS BUSULFAN

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Treatment of chronic myeloid leukemia • Part of the myeloablative preparative regime before hematopoietic stem cell Optimum sampling time As required to determine AUC transplantation (see Monitoring Therapy) ANTINEOPLASTICS Time to peak ~1.0 hour for oral therapy MODE OF ACTION • DNA alkylating agent Route of elimination Hepatic metabolism

USUAL DOSE AND DOSE INTERVAL Elimination half-life 2-3 hours • Chronic myeloid leukemia: induction of remission 60 mg/kg daily by mouth Time to steady state ~12 hours (maximum 4 mg); maintenance usually 0.5-2.0 mg daily Protein binding ~30% • Myeloablation: consult product literature Target range Target 6h AUC is 900-1500 mmol/L x min FACTORS AFFECTING CONCENTRATION (see Monitoring Therapy) • Significant interpatient variability in pharmacokinetics • Metabolized via glutathione conjugation to inactive metabolites • Clearance decreased by acetaminophen, increased by phenytoin

TOXIC EFFECTS • Tumor lysis syndrome • Nausea and vomiting • Bone marrow suppression • Hepatic veno-occlusive disease • Pulmonary fibrosis • Seizures

MONITORING THERAPY • Monitor liver function • Exposure to busulfan is typically monitored by estimating the area under the concentration-time curve (AUC) by measurement of several serum concentrations over a 6 hour time interval; this may be converted to an average steady-state concentration by dividing the AUC by the dose interval • Target 6 hours AUC is 900-1500 mmol/L x min

99 100 BACK TABLE TO OF CONTENTS METHOTREXATE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • As part of combined anticancer drug regimes • Psoriasis Optimum sampling time As required by protocol, often 24, 48 and (if • Crohn’s disease necessary) 72 hours post high-dose therapy ANTINEOPLASTICS • Rheumatoid arthritis and other autoimmune diseases Time to peak ~1 hour for low-dose oral therapy

MODE OF ACTION Route of elimination ~Predominantly renal excretion, ~90% in high-dose • Antimetabolite (inhibits dihydrofolate reductase) — in cancer, inhibits synthesis regimes of DNA, RNA, thymidylates and proteins; in rheumatoid arthritis, multiple Elimination half-life 5-9 hours (less if urine alkalinized) mechanisms including inhibition of purine metabolism, inhibition of T cell activation, selective downregulation of B cells and inhibition of binding of Time to steady state 1-2 days of chronic low dosing interleukin 1-beta to its cell surface receptor Protein binding ~50% USUAL DOSE AND DOSE INTERVAL • Dosing in anticancer regimens varies depending on the protocol Target range < 0.5-1.0 μmol/L (< 225-450 μg/L) 48 hours after high-dose therapy or according to protocol Crohn’s disease: intramuscular injection of 25 mg to induce remission, • (the convention is to use molar SI rather than then 15 mg weekly maintenance mass SI units for methotrexate concentrations) • Rheumatoid arthritis: – Moderate to severe: orally 7.5 mg weekly, adjusted according to response to a maximum of 20 mg weekly – Severe: subcutaneous, intramuscular or intravenously 7.5 mg weekly, increased by 2.5 mg weekly to a maximum of 25 mg weekly • Psoriasis: oral, intramuscular or intravenously 2.5-10 mg once weekly, adjusted in steps of 2.5-5.0 mg at intervals of >1 week; usual dose 7.5-15.0 mg once weekly, maximum 30 mg weekly

FACTORS AFFECTING CONCENTRATION • Triphasic elimination – distribution, renal elimination, elimination from intracellular distribution • Polyglutamate metabolites accumulate intracellularly

TOXIC EFFECTS • Kills rapidly-dividing cells (e.g., bone marrow: degree related to dose) • Nephrotoxic in high doses • Reversible hepatotoxicity (monitor procollagen III peptide) • Cirrhosis on chronic low dosing

MONITORING THERAPY • In high dose (i.e., anticancer therapy), there is a need to determine whether leucovorin (calcium folinate) rescue is necessary • In low dose, monitor white cell counts and hepatorenal function – methotrexate concentration monitoring unnecessary

101 102 BACK TABLE TO OF CONTENTS ANTIRETROVIRALS

ANTIRETROVIRALS

103 104 BACK TABLE TO OF CONTENTS ANTIRETROVIRALS

CLINICAL USE • Management of infection by human immunodeficiency virus (HIV)

MODE OF ACTION ANTIRETROVIRALS • Several classes of drugs are used in the management of HIV infection: – Nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine, abacavir, didanosine, emtricitabine, lamivudine, stavudine and tenofovir) – Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, etravirine, nevirapine and rilpivirine) – Protease inhibitors (PIs) (e.g., atazanavir, darunavir, fosamprenavir, indinavir, ritonavir, saquinavir and tipranavir) – Fusion inhibitors (e.g., enfuvirtide); entry inhibitors (e.g., maraviroc); integrase inhibitors (e.g., raltegravir)

USUAL DOSE AND DOSE INTERVAL • See product literature for specific drugs

FACTORS AFFECTING CONCENTRATION • NNRTIs have highly variable pharmacokinetics (metabolized by CYP2B6) • PIs also have highly variable pharmacokinetics • NRTIs are prodrugs that require activation by intracellular phosphorylation

TOXIC EFFECTS • See literature for individual drugs

MONITORING THERAPY • NRTIs are prodrugs and serum NRTI concentrations do not correlate with clinical effect; NRTIs are not suitable for drug monitoring • Therapeutic monitoring for NNRTIs and PIs may have an important role in individualizing therapy in high-risk patients or those with PI resistance • Concentrations are normally monitored in trough samples

105 106 BACK TABLE TO OF CONTENTS BRONCHODILATOR, ANALEPTIC BRONCHODILATOR, ANALEPTIC BRONCHODILATOR, THEOPHYLLINE

CAFFEINE

107 108 BACK TABLE TO OF CONTENTS THEOPHYLLINE

CLINICAL USE • Asthma/stable chronic obstructive pulmonary disease: no longer a first- or KEY PHARMACOKINETIC PARAMETERS second-line drug in chronic asthma but still useful in patients who have difficulty with inhalers and those with predominantly nocturnal symptoms Optimum sampling time Trough: immediately before next dose Peak: 4-8 hours post-dose (modified release MODE OF ACTION preparations) • Relaxes smooth muscle and relieves/prevents bronchoconstriction 2 hours post-dose (rapid-release) USUAL DOSE AND DOSE INTERVAL Time to peak 1-2 hours post-dose (rapid-release) • Modified release preparations: 200-500 mg every 12 hours; children 4-8 hours post-dose (modified release)

2-6 years: 60-120 mg every 12 hours; children 6-12 years: 125-250 mg ANALEPTIC BRONCHODILATOR, every 12 hours Route of elimination Hepatic metabolism (<20% renally) • Rate of absorption from modified-release preparations can vary between Elimination half-life 3-9 hours brands – be aware when switching brands Time to steady state 2-3 days (oral dosing, adults) • NB aminophylline preparations are the EDTA salt of theophylline and are approximately 80% theophylline by weight Protein binding ~50% Target range 10-20 mg/L (55-110 μmol/L) FACTORS AFFECTING CONCENTRATION • Metabolized to 1,3 dimethyluric acid in the liver (CYP1A2 and CYP2E1) • Rate of metabolism affected by many factors (e.g., hepatic disease, other drugs, dietary factors, smoking) TYPICAL ADULT DOSES (mg/d) TARGET RANGE (mg/L) • First-order elimination kinetics at target concentrations, zero-order at higher (mg/L) (µmol/L) concentrations 1000 1000 • Concentrations increased in heart failure, cirrhosis and viral infections and by erythromycin, cimetidine, ciprofloxacin • Concentrations decreased in smokers, chronic alcoholics and by drugs that 800 induce hepatic metabolism (e.g., phenytoin, carbamazepine, rifampicin)

TOXIC EFFECTS 600 • Side effects relatively frequent 20 110 • Mild/moderate effects (nausea, headache, jitteriness) are common within the 400 target range 400 • More serious effects (tremor, agitation, insomnia, diarrhea, palpitations, tachycardia, cardiac arrhythmias, seizures, cardiorespiratory arrest) occur with increasing frequency at plasma concentrations above 20 mg/L 200 10 55 (110 μmol/L)

MONITORING THERAPY 0 0 0 • Poor correlation between dose and plasma concentration due to variation in Adults Asthma (healthy, rate of metabolism nonsmokers) • Monitoring useful in initial dosage optimization and in confirming toxicity and monitoring overdose

109 110 BACK TABLE TO OF CONTENTS CAFFEINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Used in neonates to treat apnea of prematurity (in preference to theophylline as dose regimes are similar and effects are more predictable) Optimum sampling time Pre-dose (trough sample)

MODE OF ACTION Time to peak Rapid on IV • Stimulates central nervous system (CNS), relaxes smooth muscle and Route of elimination Renal (in neonates) relieves/prevents bronchoconstriction Elimination half-life 72-96 hours (range 40-230 hours) (neonates) USUAL DOSE AND DOSE INTERVAL Time to steady state N/A • Premature neonates, as caffeine citrate: loading 20 mg/kg, by mouth or by ANALEPTIC BRONCHODILATOR, intravenous infusion over 30 minutes; maintenance 5 mg/kg once daily by Protein binding 30-40% intravenous infusion over 10 minutes or by mouth starting 24 hours after initial dose (maximum 10mg/kg daily) Target range 5-20 mg/L (25-100 μmol/L) (in neonatal apnea)

FACTORS AFFECTING CONCENTRATION • Metabolized in liver in adults • Elimination prolonged in neonates due to immaturity of CYP1A2 • Parent drug is predominantly excreted renally in the first three months of life TARGET RANGE

TOXIC EFFECTS (mg/L) (µmol/L) • CNS effects – restlessness, tremor, seizures • Cardiovascular – tachycardia and fibrillation • Produces much less tachycardia and fewer fits than theophylline 20 100

MONITORING THERAPY • The much lower toxicity and more predictable pharmacokinetics of caffeine compared to theophylline combine to make therapeutic monitoring unnecessary; may be useful in cases of inadequate response on standard dose regimes or in confirming toxicity

5 25

0 0 Neonatal apnea

111 112 BACK TABLE TO OF CONTENTS CARDIAC AGENTS

CARDIAC AGENTS

ANTI-ARRHYTHMICS

AMIODARONE

DISOPYRAMIDE

FLECAINIDE

LIDOCAINE

CARDIAC GLYCOSIDES

DIGOXIN

113 114 BACK TABLE TO OF CONTENTS AMIODARONE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Treatment of cardiac arrhythmias when other drugs are ineffective or contraindicated • May be used for all types of tachyarrhythmias of paroxysmal nature including Optimum sampling time Pre-dose (trough sample)) supraventricular, nodal and ventricular tachycardias and ventricular fibrillation, CARDIAC AGENTS atrial flutter and fibrillation and tachyarrhythmias associated with Wolff-Parkinson- Time to peak 5 hours (oral) White syndrome Route of elimination Hepatic metabolism • Treatment should be initiated and monitored under hospital or specialist supervision Elimination half-life 50 days MODE OF ACTION • Class 3 anti-arrhythmic agent - prolongs phase 3 of cardiac action potential, slows Time to steady state Months conduction rate (also has beta-blocker activity) Protein binding >98% USUAL DOSE AND DOSE INTERVAL Target range 0.5-2.5 mg/L (0.7-3.7 μmol/L) • Oral: 200 mg three times daily for one week, reducing to 200 mg twice daily for a further week; maintenance: 200 mg once daily or the minimum needed to control arrhythmia • IV via central venous catheter: 5 mg/kg over 20-120 minutes with ECG monitoring, then according to response (maximum 1.2 g in 24 hours)

FACTORS AFFECTING CONCENTRATION • Very large volume of distribution — when given orally, takes days to suppress ventricular tachycardias; loading dose required • Very long elimination half-life TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Extensively metabolized on first pass through liver to mono-N-desethylamiodarone (mg/L) (µmol/L) (active, and even more lipid-soluble) 1000 • Inhibits metabolism of warfarin, digoxin and simvastatin by inhibition of CYP isoenzymes – a range of other drugs are affected • Metabolism of amiodarone affected by inhibitors of metabolism such as cimetidine and 800 grapefruit juice (and many others — consult literature)

TOXIC EFFECTS 600 • Toxicity related to dosage and duration of treatment 600 • Pulmonary toxicity is the most serious adverse effect (cough, dyspnea, respiratory distress) • Thyroid abnormalities in around 10% of patients on long-term treatment 400 2.5 3.7 (hypothyroidism 2-4 times more common than hyperthyroidism); check thyroid function before treatment and every 6 months • Photosensitivity and corneal deposits common 200 200 • Cardiac toxicity and hepatotoxicity rare — check liver function before treatment 0.5 0.7 MONITORING THERAPY 0 0 0 • Most patients do not need monitoring; if monitoring is performed there is no additional benefit in measuring the desethyl metabolite • Monitoring in some patients may help differentiate treatment failure from poor adherence or suboptimal dosing

115 116 BACK TABLE TO OF CONTENTS DISOPYRAMIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • To control supraventricular and ventricular arrhythmias after myocardial infarction (by intravenous injection) – but impairs cardiac contractility Optimum sampling time Pre-dose (trough sample)) CARDIAC AGENTS • Oral administration limited by antimuscarinic effect – caution in prostatic enlargement and susceptibility to open-angle glaucoma Time to peak 2-3 hours

MODE OF ACTION Route of elimination 35-60% excreted renally Hepatic metabolism to active metabolite • Class 1a anti-arrhythmic agent — inhibits conduction by blocking sodium channels Elimination half-life 4.5-9.0 hours with normal renal function

USUAL DOSE AND DOSE INTERVAL Time to steady state 1-2 days with normal renal function • Oral: 300-800 mg daily in divided doses Protein binding 50-65% (concentration dependent) • By slow IV injection with ECG monitoring: 2 mg/kg over at least 5 minutes Target range 2-5 mg/L (6-15 mol/L) to maximum 150 mg, followed immediately by 200 mg orally, then 200 mg μ every 8 hours for 24 hours, or 400 mcg/kg per hour IV infusion, maximum 300 mg in first hour and 800 mg daily

FACTORS AFFECTING CONCENTRATION • Predominantly renal excretion • Some hepatic metabolism (CYP3A4) to active metabolite, which has TYPICAL ADULT DOSES (mg/d) TARGET RANGE approximately 25% activity of parent compound (mg/L) (µmol/L) • Phenytoin and other hepatic-inducing agents increase disopyramide 1000 clearance • Commercially available disopyramide is a racemic mixture; the S(+) isomer 800 has about twice the pharmacological effect of the R(-) isomer, and is more 800 strongly bound to protein

TOXIC EFFECTS 600 • Gastrointestinal (nausea, vomiting, diarrhea) • Cardiovascular (decreased cardiac output, conduction disturbances) 5 15 • Anticholinergic (dry mouth, blurred vision, urinary retention) 400

MONITORING THERAPY 300 • Monitoring complicated by variable protein binding – free disopyramide 200 2 6 concentrations are recommended (concentration range 0.5-2.0 mg/L) • Monitoring helpful in ensuring efficacy and avoiding toxicity, especially in patients with renal impairment 0 0 0 Adults

117 118 BACK TABLE TO OF CONTENTS FLECAINIDE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • To control serious symptomatic ventricular arrhythmias, junctional reentry tachycardia and paroxysmal atrial fibrillation Optimum sampling time Pre-dose (trough sample) CARDIAC AGENTS

MODE OF ACTION Time to peak 2-3 hours • Class 1c antiarrhythmic — reduces maximum rate of depolarization in heart Route of elimination 40-45% excreted renally muscle and slows conduction Hepatic metabolism (CYP2D6) USUAL DOSE AND DOSE INTERVAL Elimination half-life 8-14 hours • Oral: (under hospital supervision) ventricular arrhythmias, initially 100 mg Time to steady state 4-5 days twice daily (maximum 400 mg daily), reduced after 3-5 days if possible; supraventricular arrhythmias 50 mg twice daily, increased if required to Protein binding 40% maximum 300 mg daily Target range 0.2-1.0 mg/L (0.5-2.4 μmol/L) • By slow IV injection: (in hospital with ECG monitoring) 2 mg/kg over 30 minutes, maximum 150 mg, followed if required by infusion at 1.5 mg/kg per hour for the first hour, reducing to 100-250 mcg/kg per hour for up to 24 hours, maximum 600 mg in first 24 hours, then transfer to oral as above

FACTORS AFFECTING CONCENTRATION • CYP2D6 substrate – shortened half-life in extensive metabolizers TYPICAL ASULT DOSES (mg/d) TARGET RANGE • Clearance reduced in renal failure and heart failure 500 (mg/L) (µmol/L) TOXIC EFFECTS • Dizziness, visual disturbances, nausea, headache 400 400 • Cardiovascular – pro-arrhythmia, cardiac failure • On chronic therapy – hypersensitivity, systemic lupus erythematosus, agranulocytosis 300 1.0 2.4 MONITORING THERAPY • Large variability between dose and plasma concentration 200 • Most patients respond at plasma concentrations 0.2-0.6 mg/L 200

100 0.2 0.5

0 0 0 Adults

119 120 BACK TABLE TO OF CONTENTS LIDOCAINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • To control ventricular arrhythmias after myocardial infarction (MI) Optimum sampling time 2 hours after start of therapy with loading dose

• Effective in suppressing ventricular tachycardia and reducing the risk of CARDIAC AGENTS ventricular fibrillation following MI Time to peak NA • Also used as a local anaesthetic Route of elimination Hepatic metabolism to active metabolite MODE OF ACTION (<10% excreted renally) • Class 1b anti-arrhythmic — blocks sodium channels in the cardiac conduction Elimination half-life 1-2 hours system, raising depolarization threshold and reducing arrhythmia Time to steady state 8-10 hours (less with loading dose) USUAL DOSE AND DOSE INTERVAL Protein binding 60-80% (alpha-1 acid glycoprotein) • By IV injection: 100 mg bolus over a few minutes (50 mg in lighter patients or those with severely impaired circulation), followed by infusion of Target range 1.5-5.0 mg/L (6-21 μmol/L) 4 mg/min for 30 minutes, 2 mg/min for 2 hours, then 1 mg/min for up to 24 hours; ECG monitoring required

FACTORS AFFECTING CONCENTRATION • Predominantly hepatic metabolism (CYP3A4) to active metabolites (monoethylglycine xylidide and glycine xylidide) • Volume of distribution decreased in congestive heart failure and dosage TARGET RANGE requirements are lower (mg/L) (µmol/L) TOXIC EFFECTS • CNS (drowsiness, dizziness, slurred speech, paresthesia, agitation), hearing disturbances, disorientation, muscle twitching, convulsions and respiratory arrest at higher doses • Cardiovascular: may depress myocardial contractility in high doses or cause hypotension, bradycardia and cardiac arrest 5.0 21 MONITORING THERAPY • Monitoring may be helpful in ensuring efficacy and avoiding toxicity, especially in patients with circulatory impairment or liver disease

1.5 6

0 0

121 122 BACK TABLE TO OF CONTENTS DIGOXIN

CLINICAL USE • Management of certain supraventricular arrhythmias, particularly chronic atrial KEY PHARMACOKINETIC PARAMETERS flutter and fibrillation • Management of chronic cardiac failure where the dominant problem is systolic Optimum sampling time Pre-dose (trough sample) or >6 hours post-dose

dysfunction and patients remain symptomatic despite treatment with ACE inhibitor CARDIAC AGENTS and beta-blocker Time to peak 1 hour (oral, plasma) MODE OF ACTION Route of elimination 60% excreted renally • Inhibition of sodium-potassium ATPase in myocardium, increasing intracellular sodium; increases the force of cardiac contraction and increases cardiac output Elimination half-life 36 hours with normal renal function USUAL DOSE AND DOSE INTERVAL Time to steady state 7-10 days • Atrial fibrillation and flutter: rapid digitalization — 0.75-1.5 mg orally over 24 hours in divided doses; maintenance, according to renal function and loading dose, Protein binding 25% 125-250 mcg daily Target range 0.8-2.0 μg/L (1.0-2.6 nmol/L) • Heart failure, for patients in sinus rhythm, 62.5-125 mcg once daily In heart failure: 0.5-1.0 μg/L (0.6-1.3 nmol/L) FACTORS AFFECTING CONCENTRATION • Renal elimination, so extra care needed in patients with impaired renal function and in the elderly • Antacids, cholestyramine and dietary fiber decrease absorption • Enzyme inducers (e.g., phenytoin and rifampicin) increase nonrenal clearance • Small changes in dose may result in either loss of efficacy or serious adverse effects; bioavailability may vary considerably between preparations, so care needed if TYPICAL ADULT DOSES (mcg/d) TARGET RANGE changing preparation (µg/L) (nmol/L) TOXIC EFFECTS 312 • Gastrointestinal (nausea, vomiting, diarrhea or constipation, abdominal pain) • Neurological (headache, fatigue, insomnia, confusion, vertigo) • Visual disturbances (blurred vision, color casts and colored halos are classic signs 250 of digoxin toxicity) 250 • Cardiac (bradycardia, atrioventricular block, ventricular tachycardias and other arrhythmias) • Toxicity is related to drug concentration but is exacerbated by hypokalemia (take 187 care when diuretics are coadministered) • Age and the severity of heart disease are also independent risk factors for the development of toxicity 125 2.0 2.6 • Severe toxicity can be treated with anti-digoxin antibodies (DigiBind® — use may invalidate immunoassays) MONITORING THERAPY 62.5 62.5 • Blood should be taken at least 6 hours post-dose to allow distribution to occur and 0.8 1.0 ensure plasma concentrations reflect tissue concentration • Plasma digoxin and plasma potassium should be measured 0 0 0 • Lower digoxin concentrations are now recommended in heart failure Adult Endogenous substances may cross-react in digoxin immunoassays (digoxin-like normal renal • function immunoreactive substances, DLIS) and yield spuriously high results; more prevalent in the very young (particularly neonates) and the elderly

123 124 BACK TABLE TO OF CONTENTS IMMUNOSUPPRESSIVE AGENTS

CICLOSPORIN/CYCLOSPORINE AGENTS IMMUNOSUPPRESSIVE

MYCOPHENOLATE

SIROLIMUS

TACROLIMUS

125 126 BACK TABLE TO OF CONTENTS CICLOSPORIN/CYCLOSPORINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Transplantation: prevention of graft rejection following kidney, liver, heart, lung, heart-lung, bone marrow or pancreas transplants Optimum sampling time Trough (C0) or 2 hours post-dose (C2) whole • Treatment of transplant rejection in patients previously receiving other blood sample immunosuppressive agents • Prophylaxis and treatment of graft-versus-host disease Time to peak 1-6 hours • Nontransplant: treatment of severe psoriasis, atopic dermatitis, ulcerative colitis and rheumatoid arthritis when conventional therapy is ineffective or inappropriate Route of elimination Hepatic metabolism • Treatment of nephrotic syndrome <1% excreted renally IMMUNOSUPPRESSIVE AGENTS IMMUNOSUPPRESSIVE MODE OF ACTION Elimination half-life 18-25 hours • Inhibits calcineurin phosphatase and limits T-cell activation Time to steady state 2-6 days USUAL DOSE AND DOSE INTERVAL Protein binding >90% • Following transplantation (oral): 10-15 mg/kg daily for 1-2 weeks postoperatively then reduced gradually to 2-6 mg/kg daily for maintenance in two divided doses Target range Varies widely with sample time, transplant type • Dose guided by blood cyclosporine concentration and renal function and time after transplantation • In dermatology: 2.5 mg/kg daily in two divided doses increasing to 5 mg/kg daily if response not achieved, guided by renal function (measure serum creatinine) • For nephrotic syndrome: initially 5 mg/kg daily in two divided doses, reduced according to efficacy to lowest effective level according to proteinuria and serum creatinine EXAMPLE TARGET RANGES (µg/L) FOR TROUGH CYCLOSPORINE THERAPY FACTORS AFFECTING CONCENTRATION • Metabolized by CYP3A4 600 • Multiple metabolites, but no evidence that metabolites make a significant contribution to pharmacological effect • Dosage adjustment needed in hepatic disease • Widely varying pharmacokinetics between patients • Highly lipophilic – accumulates in red cells • Microemulsion formulation (Neoral®) has more reproducible absorption characteristics; Sandimmun® is administered intravenously or as an oral preparation • Bioavailability varies between oral formulations – care needed when changing 350 350 formulation 300 350 TOXIC EFFECTS 250 250 250 • Renal dysfunction is a serious adverse effect 200 200 200 • Raised blood pressure and hyperlipidemia 150 150 150 • Adverse cosmetic effects (gingival hyperplasia and hypertrichosis) • Overimmunosuppression associated with infection and neoplasia 100 100 100

MONITORING THERAPY 0 0 0 0 0 • Narrow therapeutic index and variable pharmacokinetics means that monitoring is 1 2 1 2 1 2 1 2 Bone essential for safe use of the drug Kidney Liver Heart Heart-Lung Marrow • Whole blood samples used as drug is concentrated in red cells (EDTA anticoagulant) 1 = Induction therapy (approx. ≤ 3 months after transplantation); 2 = Maintenance therapy • Recommended sample times are trough or 2 hour post-dose • Target concentrations vary with time after transplantation, transplant type, other immunosuppressives, sample time and analytical method

127 128 BACK TABLE TO OF CONTENTS MYCOPHENOLATE

CLINICAL USE • Prevention of graft rejection following kidney, liver or heart transplants in KEY PHARMACOKINETIC PARAMETERS combination with cyclosporine and corticosteroids • Also widely used in combination with tacrolimus, sirolimus and everolimus Optimum sampling time Pre-dose (trough sample) or as needed to determine AUC by algorithm MODE OF ACTION • Inhibits inosine monophosphate dehydrogenase and hence purine synthesis; blocks Time to peak 1-2 hours lymphocyte proliferation Route of elimination >90% excreted renally as glucuronide USUAL DOSE AND DOSE INTERVAL Elimination half-life 17 hours

• Mycophenolate mofetil, MMF – prodrug for mycophenolic acid (MPA): following AGENTS IMMUNOSUPPRESSIVE kidney transplantation, starting dose (oral) 1 g twice daily; following heart Time to steady state NA transplantation, starting dose (oral) 1.5 g twice daily; following liver transplantation, starting dose (IV) 1 g twice daily for four days then 1.5 g twice daily by mouth Protein binding 98% • Myfortic (mycophenolate sodium, MPS): following kidney transplantation, starting Target range Varies with transplant type, time of sample, dose 720 mg twice daily; 1 g mycophenolate mofetil is approximately equivalent to method used and other medication 720 mg mycophenolate sodium (see Monitoring Therapy) FACTORS AFFECTING CONCENTRATION • Rapidly absorbed from MMF formulation, prolonged absorption from MPS • Hydrolysed to MPA, excreted renally as glucuronide (90%) • Clearance decreases in the weeks following transplantation and MPA exposure per unit dose consequently increases • Important interaction with cyclosporine – reduction in MPA exposure when administered with cyclosporine TOXIC EFFECTS • Gastrointestinal adverse effects (nausea, vomiting, diarrhea and abdominal pain) are common (less so with enteric-coated MPS) • Increased incidence of leucopenia, anemia and thrombocytopenia • Overimmunosuppression MONITORING THERAPY • Within-patient variability for pre-dose concentrations is high and isolated pre-dose measurements should be interpreted with caution • Most monitoring experience is with the MMF formulation • Plasma (EDTA anticoagulant) or serum samples used • Trough concentrations show relatively poor correlation to the area under the drug concentration-time curve (AUC); sampling algorithms are available to estimate the total exposure • Target concentrations (pre-dose, MMF formulation) approximately 2-4 mg/L are recommended following kidney transplantation, and 1-3 mg/L following heart transplantation • Recommended AUC (0-12 hours) in the range 30-60 mg.h/L

129 130 BACK TABLE TO OF CONTENTS SIROLIMUS

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Prevention of graft rejection in kidney transplant patients, initially in combination with cyclosporine and corticosteroids, then with Optimum sampling time Pre-dose (trough sample); whole blood sample corticosteroid only Time to peak 1-2 hours MODE OF ACTION Route of elimination Hepatic metabolism 1-2% excreted renally • Inhibits T cell proliferation by binding to protein kinase (mTOR) and blocking signal transduction Elimination half-life 57-63 hours

USUAL DOSE AND DOSE INTERVAL Time to steady state 5-7 days AGENTS IMMUNOSUPPRESSIVE • Loading dose of 6 mg, then usual starting dose is 2 mg once daily in Protein binding 92% combination with cyclosporine and corticosteroid for 2-3 months; cyclosporine should then be withdrawn over 4-6 weeks, or sirolimus Target range With cyclosporine: 4-12 μg/L (4.4-13.1 nmol/L) must be stopped Off cyclosporine: 12-20μ g/L (13.1-21.9 nmol/L) (chromatographic assay – results by immunoassay • Adjust dose according to sirolimus concentration are higher) • Give sirolimus 4 hours after cyclosporine

FACTORS AFFECTING CONCENTRATION • Metabolized by CYP3A in the liver and gut to hydroxy- and demethyl- metabolites — no evidence that metabolites are active TARGET RANGE • Substrate for P-glycoprotein (μg/L) (μg/L) • When coadministered with the microemulsion formulation of cyclosporine, absorption of sirolimus is enhanced, almost doubling the effective dose (hence recommendation to give sirolimus 4 hours after cyclosporine) 20 20 • Concentrated in red cells – whole blood samples used

TOXIC EFFECTS • Hematological (anemia, leucopenia, thrombocytopenia) • Hypertriglyceridemia and hypercholesterolemia 12 12 • Lymphocele formation and impaired wound healing • Not intrinsically nephrotoxic, but prolonged use with cyclosporine/ tacrolimus has a synergistic effect on nephrotoxicity • Overimmunosuppression associated with infection and neoplasia

MONITORING THERAPY 4 • Dose is a poor predictor of drug exposure 0 0 • Particularly necessary in hepatic impairment, during treatment with Cyclosporine Off inducers or inhibitors of metabolism and after discontinuing them Cyclosporine • Whole blood (EDTA anticoagulant) samples used

131 132 BACK TABLE TO OF CONTENTS TACROLIMUS

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Prevention of graft rejection in kidney, liver and heart transplant patients • Treatment of graft rejection in patients resistant to treatment with other Optimum sampling time Pre-dose (trough sample); whole blood sample immunosuppressives Time to peak 1-3 hours • Also used in moderate-to-severe atopic eczema (in the ointment Route of elimination Hepatic metabolism <1% excreted renally formulation, Protopic®) Elimination half-life 10-20 hours MODE OF ACTION

• Inhibits calcineurin phosphatase and limits T cell activation Time to steady state 2-5 days AGENTS IMMUNOSUPPRESSIVE Protein binding >98% USUAL DOSE AND DOSE INTERVAL • Vary with type of transplant and time post-transplant; oral doses following Target range Varies with sample time, transplant type, kidney transplantation are of the order of 100-200 mcg/kg daily in two co-medication and time after transplantation divided doses (once-daily with modified release formulation, Advagraf®) typically 8-12 μg/L (10.4-15.6 nmol/L) following kidney transplantation, reducing to 5-10 μg/L FACTORS AFFECTING CONCENTRATION (6.5-13.0 nmol/L) • Metabolized by CYP3A in the liver and gut; more than 15 different metabolites identified; M2 (31-desmethyltacrolimus) is active, others show little or no bioactivity • Metabolism significantly affected by genetic polymorphism of CYP3A4/ CYP3A5 • Substrate for P-glycoprotein • Range of significant drug interactions involving induction/inhibition of CYP3A or P-glycoprotein • Concentrated in red cells – whole blood samples used

TOXIC EFFECTS • Renal dysfunction is a serious adverse effect • Hematological (anemia, leucopenia, thrombocytopenia) • Hypertriglyceridemia and hypercholesterolemia • Lymphocele formation and impaired wound healing • Overimmunosuppression associated with infection and neoplasia

MONITORING THERAPY • Dose is a poor predictor of drug exposure • Particularly necessary in hepatic impairment, during treatment with inducers or inhibitors of metabolism and after discontinuing them • Whole blood (EDTA anticoagulant) samples used

133 134 BACK TABLE TO OF CONTENTS PSYCHOACTIVE AGENTS PSYCHOACTIVE AGENTS

TRICYCLIC ANTIDEPRESSANTS

AMITRYPTILINE

OTHERS

CLOZAPINE/OLANZAPINE

FLUOXETINE

HALOPERIDOL

LITHIUM

135 136 BACK TABLE TO OF CONTENTS AMITRIPTYLINE

CLINICAL USE • Second-line antidepressant (particularly dangerous in overdose; not KEY PHARMACOKINETIC PARAMETERS recommended) • Nocturnal enuresis in children (third-line, after enuresis alarms and Optimum sampling time Pre-dose (trough sample) desmopressin; imipramine preferred) Time to peak 2-4 hours • May also be used for neuropathic pain

• May be used for migraine prophylaxis Route of elimination Extensive hepatic metabolism PSYCHOACTIVE AGENTS (<1% excreted renally) MODE OF ACTION Elimination half-life 17-40 hours • Blocks serotonin and norepinephrine uptake in the brain Time to steady state 3-8 days of chronic dosing USUAL DOSE AND DOSE INTERVAL • Depression: 75 mg daily initially (less in elderly) in divided doses or as a single Protein binding ~95% dose at night increasing slowly as necessary to 150-200 mg daily Target range Depression: 80-250 μg/L (290-900 nmol/L); sum • Neuropathic pain: 10 mg at night gradually increased to 75 mg as necessary of amitriptyline and nortriptyline • Migraine prophylaxis: 10 mg at night up to 50-75 mg as necessary; maximum 150 mg

FACTORS AFFECTING CONCENTRATION • Metabolism primarily by CYP2D6 and CYP2C19 • Pharmacogenetic variation in ability to metabolise (poor/intermediate/extensive and ultra-rapid phenotypes) TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Nortriptyline is an active metabolite and more potent inhibitor of norepinephrine uptake (μg/L) (nmol/L) • Self-induction of metabolism • Enzyme-inducing drugs increase clearance 400 TOXIC EFFECTS • Significant toxicity limits use • Sedative 300 250 900 • Dangerous in overdose, consequently not recommended in depression • Tachycardia, arrhythmias and heart block 200 200 • Hypomania • Dyskinesias • Antimuscarinic effects: dry mouth, constipation, urine retention, increased 100 80 290 intraocular pressure 75 MONITORING THERAPY 0 • Good correlation between therapeutic response and serum concentration 0 0 (amitriptyline plus notriptyline) • Depression: 50-150 μg/L (180-540 nmol/L)(amitriptyline); better to monitor the sum of amitriptyline and nortriptyline: 80-250 μg/L (290-900 nmol/L) • Monitoring not required in other conditions

137 138 BACK TABLE TO OF CONTENTS CLOZAPINE/OLANZAPINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Clozapine: schizophrenia demonstrated to be intractable to conventional and at least one other atypical antipsychotic; psychosis in Parkinson’s disease Optimum sampling time Pre-dose (trough sample) • Olanzapine: schizophrenia, mania Time to peak ~2 hours

MODE OF ACTION Route of elimination Hepatic metabolism (<10% excreted renally) PSYCHOACTIVE AGENTS • Not known - antagonism of dopamine and serotonin receptors proposed Elimination half-life 9-17 hours (clozapine); 21-54 hours (olanzapine) USUAL DOSE AND DOSE INTERVAL Time to steady state 5-10 days of chronic dosing • Clozapine: 12.5 mg once or twice on day 1, then 25-50 mg on day 2, increasing in 25-50 mg steps if well tolerated over 2-3 weeks up to 300 mg in divided doses; Protein binding 90-95% dosing must be incremented; administration of a standard dose to a naïve Target range Clozapine: 350-600 μg/L (1100-1840 nmol/L) individual could be fatal Olanzapine: 20-80 μg/L (65-255 nmol/L) • Olanzapine: 10 mg initially adjusted to usual range of 5-20 mg daily

FACTORS AFFECTING CONCENTRATION • Metabolized by CYP1A2 (minor: CYP2D6, CYP3A4 and CYP2C19 [clozapine]) • Norclozapine is pharmacologically active • Smoking increases clearance TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Fluvoxamine (CYP1A2 inibitor) inhibits metabolism (µg/L) (nmol/L) (µg/L) (nmol/L) TOXIC EFFECTS 400 • Clozapine: neutropenia and potentially life-threatening agranulocytosis occurs in approximately 3% of patients 600 1840 300 • Clozapine: myocarditis and cardiomyopathy, potentially life-threatening 300 • Clozapine: reaction resembling gastrointestinal obstruction reported • Weight gain • Diabetes - test fasting glucose at baseline and every 4-6 months 200 • Clozapine: prostatic hypertrophy, postural hypotension 350 1100 • Neuroleptic malignant syndrome 80 255 MONITORING THERAPY 100 • Therapeutic effect may take weeks or months to occur 20 • Clozapine: MUST monitor differential blood counts due to risk of neutropenia 20 65 and agranulocytosis 12.5 5 0 0 0 0 0 • Optimization of dose through serum concentration monitoring is necessary as Clozapine Olanzapine Clozapine Olanzapine full therapeutic effect takes time to develop • Serum concentrations related to therapeutic and side effects

139 140 BACK TABLE TO OF CONTENTS FLUOXETINE

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • First-line antidepressant (major depression) • Obsessive-compulsive disorder Optimum sampling time Pre-dose (trough sample) • Bulimia nervosa Time to peak 6-8 hours

MODE OF ACTION Route of elimination Hepatic metabolism (<5% excreted renally) PSYCHOACTIVE AGENTS • Selective serotonin reuptake inhibitor (SSRI) Elimination half-life Fluoxetine: 24-144 hours Norfluoxetine: 170-360 hours USUAL DOSE AND DOSE INTERVAL • Depression: 20 mg daily increased after 3-4 weeks as necessary to a Time to steady state 3-4 weeks of chronic dosing maximum of 60 mg daily Protein binding ~95% • Obsessive-compulsive disorder: 20 mg daily to a maximum of 60 mg daily if required; if no response after 10 weeks reconsider treatment Target range Tentatively 120-500 mg/L (0.39-1.62 mmol/L) (combined fluoxetine and norfluoxetine) • Bulimia: 60 mg daily as single or divided dose

FACTORS AFFECTING CONCENTRATION • Prescribed as racemate • Desmethyl metabolite, norfluoxetine, pharmacologically active and has a half-life four times that of fluoxetine TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Fluoxetine inhibits CYP2C9, norfluoxetine inhibits CYP3A4, (inhibiting, for example, carbamazepine and phenytoin clearance, respectively) (µg/L) (µmol/L) • CYP2D6 and CYP2C19

TOXIC EFFECTS • Do not use with monoamine oxidase inhibitors (potentially fatal interaction) • Care with tricyclic antidepressants 60 • Hyponatremia 60 • Gastrointestinal disturbances are common (nausea, dyspepsia, diarrhea) • Anorexia 40 500 1.62 • Dyskinesias

MONITORING THERAPY 20 • No evidence that monitoring is necessary, but any investigations of 20 120 0.39 concentration-effect relationships should combine fluoxetine and norfluoxetine concentrations 0 0 0 Depression (ﬂuoxetine plus norﬂuoxetine)

141 142 BACK TABLE TO OF CONTENTS HALOPERIDOL

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Antipsychotic: schizophrenia and other psychoses • Mania Optimum sampling time Pre-dose (trough sample) • Violent/dangerous impulsive behavior Time to peak ~2 hours • Agitation and restlessness in the elderly

Route of elimination Hepatic metabolism (<1% excreted renally) PSYCHOACTIVE AGENTS • Anxiety (short-term adjunctive management) • Intractable hiccup Elimination half-life ~20 hours (reduced metabolite accumulates in CYP2D6 poor metabolizers) • Palliative nausea and vomiting Time to steady state 5-7 days of chronic dosing MODE OF ACTION • Blocks effects of dopamine and increases turnover rate Protein binding ~90% Target range Haloperidol: 5-16 mg/L (13-42 nmol/L) USUAL DOSE AND DOSE INTERVAL Reduced haloperidol 10-80 mg/L (26-210 nmol/L) • Psychoses: by mouth, initially 2-20 mg as a single dose or in divided doses, Toxic concentrations vary between patients then 1-3 mg three times daily, adjusted according to response (maximum 20 mg daily in divided doses) Elderly/debilitated: initially half dose • Agitation and restlessness: 0.5-1.0 mg once or twice daily • Anxiety: 0.5 mg twice daily TYPICAL ADULT DOSES (mg/d) TARGET RANGE • Intractable hiccup: 1.5 mg three times daily adjusted according to response (HALOPERIDOL) (µg/L) (nmol/L) • Palliative nausea and vomiting: 1.5 mg once or twice daily, up to 5-10 mg daily in divided doses if necessary

FACTORS AFFECTING CONCENTRATION • Metabolized by reduction of the ketone group to an alcohol, this is backconverted to haloperidol by CYP2D6 — genotype is important as poor metabolizers will accumulate the reduced metabolite 16 42 • Reduced metabolite has 20% of the activity of the parent drug, but has a longer half-life (~70 hours) 10 TOXIC EFFECTS 10 • Extrapyramidal side effects • Irreversible tardive dyskinesia 5 • Dystonia and akathisia a particular risk in thyrotoxicosis 5 13 • Hyponatremia 3

MONITORING THERAPY 0 0 0 • Monitoring is appropriate in psychoses management; monitoring of the reduced metabolite to avoid accumulation of the reduced metabolite if CYP2D6 genotyping has not been performed

143 144 BACK TABLE TO OF CONTENTS LITHIUM

CLINICAL USE KEY PHARMACOKINETIC PARAMETERS • Treatment and prophylaxis of mania, bipolar disorder and recurrent depression • Aggressive or self-mutilating behavior Optimum sampling time 12 hours post-dose MODE OF ACTION • Specific mode of action not known; may increase tryptophan uptake and Time to peak 2-4 hours (longer with sustained-release forms) serotonin synthesis

Route of elimination Renal excretion only PSYCHOACTIVE AGENTS USUAL DOSE AND DOSE INTERVAL Elimination half-life 10-35 hours (elderly have decreased renal function • Lithium carbonate is the typical salt used: 400-1200 mg daily initially with and typically longer half-lives) serum concentration monitoring 12 hours post-dose to fall within the target range; adjust as required Time to steady state 3-7 days of chronic dosing • Elderly usually require lower doses • Once dose stabilized, switch from divided to single doses Protein binding 0% • Lithium carbonate 200 mg = lithium citrate 509 mg Target range Usually: 0.4-1.0 mmol/L FACTORS AFFECTING CONCENTRATION Elderly: 0.4-0.8 mmol/L • Wide bioavailability variation between preparations; changing therapy should Acute bipolar disorder: up to 1.2 mmol/L be monitored as for initiation of therapy (Lithium concentration is always expressed as • Lithium competes with sodium for reabsorption in renal tubules – altered mmol/L [equivalent to mEq/L]) sodium balance or fluid intake may precipitate toxicity • Interaction with diuretics – thiazides decrease excretion • Renal impairment reduces excretion TYPICAL ADULT DOSES (mg/d) TARGET RANGE (as lithium carbonate) (mmol/L) TOXIC EFFECTS • Renal impairment (risk of vicious circle as drug is renally excreted) 2000 • Hypothyroidism • Nephrogenic diabetes insipidus • Hyponatremia potentiates toxicity (avoid thiazide diuretics) 1600 • Hyperparathyroidism rarely • CNS disturbances (ataxia, tremors, lethargy, sedation, dysarthria, confusion, seizures) are an indication of toxicity 1200 1200 • Chronic dosing: – Toxicity >1.5 mmol/L requires intervention – Lithium concentrations >2.0 mmol/L consider hemodialysis 1.0 • Naïve subjects achieving the same concentrations are less likely to suffer 800 significant toxicity

MONITORING THERAPY 400 • Monitoring is vital - toxicity is related to serum concentration 400 • Check thyroid function and renal function before therapy commences and 0.4 every 3-6 months • Normal sampling time is 12 hours post-dose 0 0 • Target range is 0.4-1.0 mmol/L • Acute bipolar disorder may require concentrations up to 1.2 mmol/L • 0.8 mmol/L preferred upper end of target range • Relapses more likely below approximately 0.5 mmol/L

145 146 BACK TABLE TO OF CONTENTS GLOSSARY GLOSSARY Adherence – the extent to which a patient takes medication as Free drug concentration – the concentration of drug in a biological prescribed. fluid (e.g., plasma or serum) that is not bound to protein. The unbound drug is presumed to be the fraction which is pharmacologically active. Apparent volume of distribution – see Volume of distribution. Half-life – time required for the plasma concentration to fall to half its Area under the curve (AUC) – area beneath the plasma concentration- original value. time plot. A measure of the total exposure to drug absorbed. Loading dose – initial dose to achieve the desired plasma Bioavailability – the fraction of administered dose reaching the concentration rapidly. systemic circulation unchanged after extravascular administration. Maintenance dose – dose given at intervals to replace drug eliminated Clearance – the ability of the organs of elimination to remove a drug from the body and maintain a steady plasma concentration. from the body. Defined as the theoretical volume of blood that can be completely cleared of drug in unit time. Nonlinear (zero order) elimination – elimination process in which excretion or metabolism is capacity-limited and may become saturated. Compliance – see Adherence. Elimination then proceeds at a fixed rate independent of plasma drug Concordance – see Adherence. concentration. Process is described by Michaelis-Menten kinetics.

Distribution – the movement of a drug within the intravascular Peak serum concentration – the maximum serum concentration space and between the intravascular space and extravascular fluids attained following administration of a dose of drug. and tissues. Pharmacodynamics – study of the biochemical and physiological Elimination – irreversible loss of drug from the body by metabolism effects of drugs and their mechanisms of action. Describes the or excretion. relationship between the drug concentration at the site of action and the pharmacological response. Elimination half-life – see Half-life. Pharmacokinetics – study of the absorption, distribution, metabolism Elimination rate constant – for drugs which follow linear, first-order and excretion of a drug and its metabolites in the body and of the elimination processes, the fraction of the total amount of drug in the mathematical relationships which can be used to describe or predict body which is eliminated per unit of time. these processes. First-order elimination – elimination process in which the rate of Plateau – stable concentration of drug in plasma found at steady state. elimination is proportional to the plasma drug concentration. Steady state – point at which the rate of administration of drug is First-pass metabolism – removal of drug from the plasma after balanced by the rate of elimination. absorption and before reaching the systemic circulation, usually by the liver.

147 148 BACK TABLE TO OF CONTENTS GLOSSARY, continued COMMON TRADE NAMES (not a comprehensive listing for all countries) Target range – the range of plasma concentrations over which a drug exhibits therapeutic benefit with minimal toxicity in the majority TRADE NAME APPROVED NAME of patients. Advagraf®...... Tacrolimus

Therapeutic index or therapeutic ratio – the margin between Amikin®...... Amikacin the concentration at which a drug exerts a therapeutic effect and the Aptiom®...... Eslicarbazepine COMMON TRADE NAMES concentration at which toxic effects are observed. Banzel®...... Rufinamide Therapeutic range – see Target range. Busilvex®...... Busulfan Trough serum concentration – the concentration of drug in the Busulfex®...... Busulfan serum immediately before the next dose is given, usually representing Cafcit®...... Caffeine the lowest concentration achieved on that dose regimen. Camcolit® ...... Lithium Volume of distribution –the volume of a compartment necessary Carbagen® ...... Carbamazepine to account for the total amount of drug in the body if it were present CellCept®...... Mycophenolate throughout the compartment at the same concentration as found in Cidomycin® ...... Gentamicin the plasma. Clozaril® ...... Clozapine Cordarone® ...... Amiodarone Depacon®...... Valproate Depakene® ...... Valproate Depakote® ...... Valproate Dilantin® ...... Phenytoin Emeside®...... Ethosuximide Epanutin®...... Phenytoin Epilim®...... Valproate Eskalith® ...... Lithium Felbatol®...... Felbamate Gabitril® ...... Tiagabine Garamycin®...... Gentamicin Gengraf®...... Cyclosporine

149 150 BACK TABLE TO OF CONTENTS COMMON TRADE NAMES, continued (not a comprehensive listing for all countries)

TRADE NAME APPROVED NAME TRADE NAME APPROVED NAME Genticin®...... Gentamicin Prozac®...... Fluoxetine Haldol®...... Haloperidol Rapamune®...... Sirolimus

Inovelon®...... Rufinamide Rivotril®...... Clonazepam COMMON TRADE NAMES Keppra®...... Levetiracetam Rythmodan®...... Disopyramide Klonopin®...... Clonazepam Sabril® ...... Vigabatrin Lamictal® ...... Lamotrigine Sandimmun® ...... Cyclosporine Lanoxin® ...... Digoxin Serenace® ...... Haloperidol Lithobid®...... Lithium Sevredol®...... Morphine Lyphocin®...... Vancomycin Slo-Phyllin®...... Theophylline Lyrica®...... Pregabalin Subutex®...... Buprenorphine MS Contin®/MST Continus®...... Morphine Taloxa® ...... Felbamate Myfortic®...... Mycophenolate Tambocor® ...... Flecainide Myleran®...... Busulfan Targocid®...... Teicoplanin Mysoline®...... Primidone Tegretol®...... Carbamazepine Neoral®...... Cyclosporine Temgesic®...... Buprenorphine Neurontin®...... Gabapentin Theo-Dur®...... Theophylline Norpace®...... Disopyramide Tobi® ...... Tobramycin Noxafil®...... Posoconazole Tobrex®...... Tobramycin Nuelin®...... Theophylline Topamax®...... Topiramate Oramorph®...... Morphine Trileptal®...... Oxcarbazepine Phenytek®...... Phenytoin Tylenol® ...... Acetaminophen Phyllocontin®...... Theophylline Uniphyllin® ...... Theophylline Priadel® ...... Lithium Vancocin®...... Vancomycin Pro-Epanutin®...... Fosphenytoin Vfend®...... Voriconazole Prograf® ...... Tacrolimus Vimpat®...... Lacosamide

151 152 BACK TABLE TO OF CONTENTS COMMON TRADE NAMES, continued (not a comprehensive listing for all countries)

TRADE NAME APPROVED NAME Xylocaine®...... Lidocaine Zarontin® ...... Ethosuximide

Zebinix®...... Eslicarbazepine COMMON TRADE NAMES Zomorph®...... Morphine Zonegran®...... Zonisamide Zyprexa®...... Olanzapine