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Epilepsia, **(*):1–38, 2008 doi: 10.1111/j.1528-1167.2008.01561.x SPECIAL REPORT Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies ∗ Philip N. Patsalos, †David J. Berry, ‡Blaise F. D. Bourgeois, §James C. Cloyd, ¶Tracy A. Glauser, #Svein I. Johannessen, $
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   Epilepsia,  ** (*):1–38, 2008doi: 10.1111/j.1528-1167.2008.01561.x SPECIAL REPORT Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by thesubcommission on therapeutic drug monitoring, ILAECommission on Therapeutic Strategies ∗ Philip N. Patsalos,  † David J. Berry,  ‡ Blaise F. D. Bourgeois,  §  James C. Cloyd, ¶ Tracy A. Glauser, #Svein I. Johannessen, $Ilo E. Leppik,  ∗∗ Torbj¨orn Tomson,and  †† Emilio Perucca ∗ Institute of Neurology/The National Hospital for Neurology and Neurosurgery, London and The Chalfont Centrefor Epilepsy, Chalfont St Peter, United Kingdom;  † Medical Toxicology Unit, Guys and St. Thomas’ Hospital, London,United Kingdom;  ‡ Harvard Medical School, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.;  § Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, U.S.A.;  ¶ Children’sHospital Medical Center, Department of Neurology, Cincinnati, Ohio, U.S.A.; #The National Center for Epilepsy,Sandvika, Division of Clinical Neuroscience, Rikshospitalet University Hospital, Oslo, Norway; $University of Minnesota, Minneapolis, Minnesota, U.S.A.;  ∗∗ Karolinska University Hospital, Stockholm, Sweden; and  †† Instituteof Neurology, IRCCS C. Mondino Foundation and Clinical Pharmacology Unit, University of Pavia, Pavia, Italy S UMMARY Although no randomized studies have demon-strated a positive impact of therapeutic drug mon-itoring (TDM) on clinical outcome in epilepsy, evi-dence from nonrandomized studies and everydayclinical experience does indicate that measuringserum concentrations of old and new generationantiepileptic drugs (AEDs) can have a valuable rolein guiding patient management provided that con-centrations are measured with a clear indicationand are interpreted critically, taking into accountthe whole clinical context. Situations in which AEDmeasurements are most likely to be of benefit in-clude (1) when a person has attained the desiredclinical outcome, to establish an individual thera-peutic concentration which can be used at subse-quent times to assess potential causes for a changein drug response; (2) as an aid in the diagnosisof clinical toxicity; (3) to assess compliance, par-ticularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjust-ment in situations associated with increased phar-macokinetic variability (e.g., children, the elderly,patientswithassociateddiseases,drugformulationchanges); (5) when a potentially important phar-macokinetic change is anticipated (e.g., in preg-nancy, or when an interacting drug is added or re-moved); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particu-larly phenytoin.KEY WORDS: Children, Elderly, Pregnancy, Drugcompliance, Saliva, Pharmacokinetics. Background and historical introduction Since drug action depends on the availability of the ac-tive principle at receptor sites, knowledge of the phar-macokinetic properties of the medication used is impor- Accepted January 28, 2008; Online Early publication xxxxxxxx.Address correspondence to Professor Philip N. Patsalos, Chalfont Cen-tre for Epilepsy, Pharmacology and Therapeutics Unit, Chesham Lane,Buckinghamshire, SL9 0RJ, U.K. E-mail: P.Patsalos@ion.ucl.ac.uk Blackwell Publishing, Inc. C   2008 International League Against Epilepsy tant for optimal treatment. The treatment of epilepsy wasone of the first areas to benefit from pharmacokineticstudies.Both physicians and pharmacologists have long been in-terested in ascertaining why the same drug dosage is effec-tive in some patients but not in others. In the past, the mosteffective dosage for an individual was established by trialand error. The development of technology for quantifyingdrugconcentrationsinbiologicalfluidshas,however,madeit possible to study the relationship between drug dosage,1  2 P. N. Patsalos et al. drug concentration in body fluids and pharmacologiceffects, and thereby provide new insights into drug therapy.It was soon recognized that the desired therapeutic effectof many antiepileptic drugs (AEDs) was usually achievedwithinaspecificrangeofserumconcentrations(henceforthcalled “reference range”) with lower concentrations beingmore likely to produce an insufficient effect, and higherconcentrations being more often associated with adverseeffects. Therapeutic drug concentration monitoring (TDM)was initiated for a number of AEDs and used to establishoptimal therapy regimens for individual patients. This ap-proach has provided physicians with a valuable tool to fur-ther understand why patients do not respond satisfactorilyto a particular dose. Furthermore, TDM has made it possi-ble to assess noncompliance and to study the variation inpharmacokinetics that occurs between individuals and thefactors responsible for such variation.The initial studies in this area were conducted in thefifties and early sixties by Buchthal and his group, who re-lated serum concentrations of phenytoin and phenobarbitalto seizure control and central nervous system (CNS) toxi-city (Buchthal & Svensmark, 1960). Subsequently, a vastnumber of pharmacokinetic studies on AEDs were pub-lished. Results from this research have been presented atseveral specialized symposia and workshops. One of thefirst was held in Scottsdale, Arizona, USA, 1971, to createan authoritative reference book about AEDs, the first edi-tion of a now much appreciated series, Antiepileptic Drugs(Woodbury et al., 1972). It was anticipated that new in-formation concerning the relationship of serum concentra-tions to seizure control and toxicity would improve utiliza-tion of AEDs, and a multidisciplinary cooperation of phar-macologists, pharmacists, toxicologists, neurologists, andpediatricians was initiated at this meeting.Between 1972 and 1979, a series of workshops knownas WODADIBOFs (Workshop on the Determination of Antiepileptic Drugs in Body Fluids) were held. Thefirst took place in Noodwijkerhout, The Netherlands, anddealt with methods for the quantitative determination of AEDs (Meijer et al., 1973). The second (Bielefeld, Ger-many, 1974) dealt with the clinical pharmacology of AEDs, including bioavailability, protein binding, distribu-tion, metabolism, elimination, drug interactions, applica-tion of new assay methods and quality of the methods(Schneider et al., 1975). The third (Exeter, England, 1976)focused on TDM, including assay methods, clinical phar-macology and clinical applications (Gardner-Thorpe et al.,1977). At the fourth workshop (Oslo, Norway, 1979) theadvantages and disadvantages of monitoring AED treat-ment were the main topics with emphasis on the influenceof age and the problems of synergism, potentiation, anddrug interactions. The quantification of epileptic manifes-tations, the influence of AEDs upon the natural history of epilepsy and methodological aspects of drug analyses werealso discussed (Johannessen et al., 1980).The need for quality control programs in drug measure-ments was recognized rapidly, since early surveys showedgreat variation of analytical results (Pippenger et al., 1978).Reliable measurements are mandatory for TDM to be of value and in 1972 the first quality control scheme forAED measurements was started in London, England byAlan Richens, and rapidly gained international participa-tion. International cooperation on quality control improvedover time and secured the analytical performance of manylaboratories engaged in TDM (Wilson et al., 1989, 1992;Richens, 1995; Williams et al., 2003). The availability of simple, accurate, reproducible, and inexpensive analyticalassays is pivotal for the successful use of TDM in patientmanagement. Objectives of this document This position paper has been prepared by an interna-tional panel of authors who in their careers have been in-strumental in developing and implementing practice pa-rameters in the field of TDM and have used TDM of AEDs in their everyday clinical practice. In 1993, the In-ternational League Against Epilepsy (ILAE) issued guide-lines for the TDM of AEDs in order to promote a moreappropriate application of the technique (Commission onAntiepileptic Drugs, 1993). However, since 1993 knowl-edge has advanced considerably and many new AEDs havebeen introduced, some of which are attractive candidatesfor TDM.This document is divided into three sections. The firstsection addresses the rationale for monitoring serum con-centrations of AEDs, the clarification of the concept of “reference ranges” and “therapeutic ranges” and the im-pact of TDM on clinical outcome. The second sectioncomprises a description of currently licensed AEDs (inalphabetical order) with regard to their pharmacokineticcharacteristics, interaction profiles, relationship betweendrug concentrations, and clinical effect and assay method-ologies. The third section describes specific situations inwhich TDM is likely to be particularly useful in patientmanagement.This document is not intended to provide a systematicreview on the topic. Although an extensive literature searchwas made using electronic databases and searches throughthe authors’ files, only references considered to be partic-ularly significant to illustrate specific concepts or findingsare quoted. M ONITORING  S ERUM C ONCENTRATIONS OF  AED S :R ATIONALE , I NTERPRETATION AND I MPACT ON  C LINICAL  O UTCOME Rationale Although individualization of dose is essential inepilepsy therapy, identification of the optimal dose on  Epilepsia ,  ** (*):1–38, 2008doi: 10.1111/j.1528-1167.2008.01561.x  3 Therapeutic Monitoring of Antiepileptic Drugs purely clinical grounds can be difficult. There are manyreasons for this: (1) since AED treatment is prophylacticand seizures occur at irregular intervals, it is often difficultto determine rapidly whether the prescribed dosage will besufficient to produce long-term seizure control; (2) clini-cal symptoms and signs of toxicity may be subtle, or dif-ficult to differentiate from the manifestations of underly-ing disorders; (3) there are no direct laboratory markers forclinical efficacy or for the most common manifestations of AED toxicity, such as adverse CNS effects.TDM seeks to optimize patient outcome by managingtheir medication regimen with the assistance of informa-tion on the concentration of AEDs in serum or plasma(serum and plasma usually can be used interchangeablyfor TDM, although it is preferable for each laboratory touse consistently one or the other). To this end, TDM seeksto optimize the seizure suppressing effects of AEDs whilstminimizing their adverse effects. The concept rests on theassumption that clinical effects correlate better with drugconcentrations than with dose. There are some require-ments that need to be fulfilled in part or in full to obtaina meaningful stable relationship between the serum con-centration of a drug and its effect. The drug should havea rapidly reversible action and development of toleranceshould not occur at its site of action. It should act per seand not through metabolites (but, if so, metabolites shouldbe measured), and the concentration of the drug at the siteof sampling (usually blood) should ideally be highly corre-lated with the concentration of the drug at receptor sites.Although the epilepsy-related rationale and indeed theindications for TDM are similar for all AEDs, the use-fulness of these measurements will vary between AEDsdepending on their pharmacological properties. TDM islikely to be of particular value for drugs that exhibit pro-nounced intra- or interindividual variability in pharmacoki-netics. Irrespective of the properties of the monitored drug,TDM is also expected to be helpful in ascertaining drugcompliance, in attributing toxicity to drug treatment, andin managing overdoses and drug interactions. Terminology and definitions Terms such as “reference ranges,” “therapeutic ranges,”“optimal ranges,” “desirable ranges,” “effective ranges,”“targetranges,”and“targetconcentrations”havebeenvari-ably used in the TDM literature, either interchangeably orwith different meanings. Since this has resulted in muchconfusion, providing clear definitions is essential.In the present paper, the recommendation is made thattwo separate terms be used to define drug concentrationranges in relation to their clinical effects. The “referencerange” can be defined as a range of drug concentrations,which is quoted by a laboratory and specifies a lower limitbelow which a therapeutic response is relatively unlikelyto occur, and an upper limit above which toxicity is rel-atively likely to occur. The aim of much TDM researchhas been to provide a reference range which laboratoriescan quote and which clinicians can use as a guide. As dis-cussed in more detail in the sections below, clinicians usingreference ranges should be aware that, because of individ-ual variation, many patients can achieve therapeutic benefitat serum drug concentrations outside these ranges. In otherwords, the reference range is not a “therapeutic range”: thelatter can be defined, for the purposes of the present pa-per, as the range of drug concentrations which is associ-ated with the best achievable response in a given person,and therefore it can only be determined for the individualsince the range will differ in different individuals. How-ever, if the reference range is a result of extensive and reli-ableresearch,formanyindividualpatientstheirtherapeuticrange willliewithin,oratleastclose,tothereferencerangequoted by the laboratory. Some individuals, however, willderive optimal benefit at concentrations outside the refer-ence range and some will have toxic effects within thisrange. Concentrations lying within the reference range arenot “normal” because the “normal” concentration of a drugin a living organism is zero. Concentrations lying withinthe reference range may not necessarily be “therapeutic,”“effective,” or “optimal” and therefore it is recommendedthat these adjectives not be used when reporting the results.The correct reporting terminology should be “The resultlies within/above/below the reference range.” Historical perspective on reference ranges of AEDs The reference range has been a controversial concept inTDM, partly because it was initially defined on the ba-sis of limited data for individual AEDs. This can be illus-trated with phenytoin as an example, although phenytoinwithout doubt is the AED with the best-documented rela-tionship between serum concentration and clinical effect.The generally quoted range for phenytoin (10–20 mg/L,40–79  µ mol/L ∗ ) srcinates from the pioneering work of Buchthal and collaborators (Buchthal et al., 1960). Eightypatients with at least one “grand mal” seizure per week,despite use of phenobarbital in combination with pheny-toin, were followed up. Only 6 out of 24 (25%) improvedat serum phenytoin concentrations below 10 mg/L, while21 out of 27 patients (77%) improved at concentrations ex-ceeding 10 mg/L. The majority of patients with concen-trations above 30 mg/L experienced adverse effects. Theupper limit of the range was partly based on the resultsof another study by Kutt et al. (1964), who reported nys-tagmus among all patients with serum phenytoin concen-trations above 20 mg/L. Ataxia was observed at phenytoinconcentrations above 30 mg/L and in all patients at con-centrations exceeding 40 mg/L. ∗ Molar digits have not been rounded up to ensure precise mathematicalcorrespondence to the mg/L digits. However, laboratories quoting pref-erentially molar units may decide to round them up or down. Conversionfactors from mg/L to µ mol/L (and vice versa) for each of the major AEDsare reported in Table 1.  Epilepsia ,  ** (*):1–38, 2008doi: 10.1111/j.1528-1167.2008.01561.x  4 P. N. Patsalos et al. A prospective study of 32 outpatients with “grand mal”seizures gave further support to the quoted reference range(Lund, 1974). These patients, half of whom receivedphenytoin in combination with other AEDs, had at leastone grand mal seizure per 2 months at inclusion, despitetreatment with phenytoin for more than a year. They werefollowed up for 3 years, during which the mean pheny-toin serum concentration was gradually increased from6 mg/L in the first year to 12 mg/L in the second and15 mg/L in the third. The annual mean number of “grandmal” seizures per patient decreased in parallel from 5.8 to4.1, and 1.6, respectively. Cerebellar adverse effects wererare and noted only in relation to phenytoin concentrationsabove 20 mg/L. The results thus corroborated previousfindings and supported a reference range of 10–20 mg/L.However, these early studies were all conducted in patientswith severe epilepsy and frequent generalized tonic–clonicseizures despite a long history of epilepsy and several treat-ment attempts often with phenytoin. Patients with easy-to-treat epilepsy had thus been excluded. Subsequent studiesdemonstrated that the seizure type as well as the sever-ity of the epilepsy has an influence on which serum con-centration is needed to obtain seizure control (Schmidt &Haenel, 1984; Schmidt et al., 1986). In a prospective study,one-third of previously untreated patients with newly diag-nosed epilepsy were controlled with phenytoin concentra-tions below the reference range (Shorvon et al., 1980). Asa consequence, the value of the lower limit of the referencerange has been seriously questioned and it has graduallybecome widely accepted that there is a considerable indi-vidual variation in what is the therapeuti c  serum concen-tration of phenytoin as well as other AEDs. The limitations of reference ranges The evidence discussed above indicates that, for allAEDs, reference ranges have purely a statistical meaning,being an estimate of the concentration interval at whichthe majority of patients showed an optimal response in avariable number of studies. Because of inherent method-ological problems with such studies, however, these rangesmay not necessarily be applicable to all patients. Most no-tably,duetothefactthatmanystudiesprovidingsupportiveevidence for reference ranges were undertaken in popula-tions with difficult-to-treat epilepsy, some of these rangesmay not describe adequately the concentration-responserelationship in patients with newly diagnosed epilepsies,who not uncommonly respond well to serum AED concen-trations below the commonly reported lower limit of therange (Feldman & Pippenger, 1976; Shorvon et al., 1978,1980;Schmidt&Haenel,1984).Basedonthis(andthefactthatsomedifficult-to-treatpatientsmayalsorespondatlowserum AED concentrations), the suggestion has been madethat “reference ranges” of AEDs be redefined by omittinga lower limit, and by simply advising physicians that theprobability of seizure control decreases with decreasingdrug concentration (Perucca & Richens, 1981). Althoughfor every drug there must be a “threshold concentration”at which no patient will show a therapeutic effect, such aconcentration is difficult to define based on available data.Even when reference ranges are redefined by omitting alowerlimit,theirinterpretationrequiresagooddealofflex-ibility. In probabilistic terms, the likelihood of seizure con-trol would be expected to increase with increasing serumconcentration, at least up to the upper limit of the range,even though it is recognized that concentrations above acertain threshold may paradoxically result in deteriorationrather than improvement in seizure control (Perucca et al.,1998). Even the upper limit of the range may vary fromone patient to another, and there are individuals who ex-perience toxic symptoms at low drug concentrations whileothers may tolerate and indeed require concentrations intothe nominally “toxic” range (Gannaway & Mawer, 1981).This has led to the recommendation that dose adjustmentsshould never be made on the basis of serum drug concen-trations alone, but should be primarily justified by care-ful assessment of the patient’s clinical state. Specifically,dosage should not be modified in patients who achievedsustained seizure freedom at serum drug concentrationsbelow the lower limit of the commonly quoted “refer-ence range” (Woo et al., 1988), nor in patients who aredoing clinically well at concentrations above this range(Gannaway & Mawer, 1981). From reference ranges to “individual therapeuticconcentrations” Given the considerable interpatient variability in theconcentration of an AED that produces optimal therapeuticresponses, the argument can be made that ultimately AEDtherapy can be bestguided byidentification ofthe “individ-ual therapeutic concentration” (Perucca, 2000). The lattercan be defined as the concentration (or range of concen-trations) which has been empirically found to produce theoptimal response in the individual patient (i.e., completeseizure control without undesired effects or, if that is notachievable, the best compromise between seizure suppres-sion and concentration-related adverse effects).In practice, the individual therapeutic concentration canbe established by determining, preferably on at least twoseparate occasions at steady state, the serum AED concen-tration once a patient has been stabilized on his/her opti-mal regimen. In a patient who had infrequent seizures be-fore starting treatment, this can only be done after a longperiod of observation, in order to be able to confirm thatremission has been really achieved. Of course, if a patientbecame free from seizures and from adverse effects on theinitially prescribed dosage, it cannot be excluded that aneven lower dosage might have been equally efficacious,and the individual therapeutic concentration measured inthat patient might therefore be an overestimate. On theother hand, if a patient needed up-titration due to his/her  Epilepsia ,  ** (*):1–38, 2008doi: 10.1111/j.1528-1167.2008.01561.x
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