Pharmac. Ther.Vol.54, pp. 297-305.1992 Printed in GreatBritain.
0163-7258/92$15.00 1992PergamonPressLtd
Associate Editor: M. J. BRODIE
R A T I O N A L USE OF ANTIEPILEPTIC D R U G LEVELS WILLIAM H. THEODORE Clinical Epilepsy Section, National Institutes of Health, Bethesda MD 20892, U.S.A.
Abstraet--Antiepileptic drug (AED) levels are obtained frequently in clinical practice, but their complex relation to seizures or drug toxicity often makes interpretation of the results difficult. Research studies have not always taken into account clinical, as well as pharmacokinetic and pharmacodynamic, factors which may influence the drug level-effect relationship. AED levels should be drawn at an appropriate time in relation to drug ingestion and clinical symptoms. Systematic investigations in selected patients, during which several levels are obtained, may be more rewarding than routine measurements in a large clinic population.
CONTENTS 1. Introduction 2. Phenobarbital 3. Phenytoin 4. Carbamazepine 5. Valproic Acid 6. Conclusion References
297 299 300 301 301 302 303
1. I N T R O D U C T I O N The unique role of antiepileptic drug (AED) level measurements in clinical management is dictated by the peculiarly intermittant nature of seizure disorders. Patients with seizures may go for weeks or months without any symptoms against which drug effects can be judged. Moreover (except in the case of children with absence), physicians treating patients with epilepsy tend not to see seizures occur and the neurological examination usually is normal. Clinical signs or symptoms of drug toxicity, such as diplopia or nystagrnus, may be intermittant. Thus, few objective (at least to the physician) measures of drug effect are available. In contrast, in patients with myasthenia gravis or Parkinson's Disease, the clinical effects of the drugs are usually obvious within several hours of dosing. The role of drug levels in conditions such as Parkinson's Disease is being increasingly recognized, but remains far less prominant than in epilepsy (Mouradian et al., 1987). Clinical measurement of AED levels became practical in the late 1950s when spectrophotometric and colorimetric assays for phenytoin (PHT) were developed (Plaa and Hine, 1956; Dill et al., 1956). These methods were sensitive to interference by phenobarbital (PB), a particularly important consideration when many patients were taking both drugs simultaneously and further modifications were devised to separate the two drugs (Glazko, 1972). An improved method designed to measure both P H T and PB in blood simultaneously was devised by Svensmark and associates and used in several important early studies of the relation of drug levels to clinical efficacy (Svensmark et al., 1960; Svensmark and Kristensen, 1963). Abbreviations--AED, antiepileptic drug; CBZ, carbamazepine; CBZ-E, carbamazepine 10,11-epoxide; CPS, complex partial seizures; GTCS, generalized tonic clonic seizures; PB, phenobarbital; PHT, phenytoin; PRM, primidone; VPA, valproic acid.
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Subsequent methods included gas and then high pressure liquid chromatography, followed by enzyme multiplied immunochemical assay (EMIT), fluorescence polarization immunoassay, noninstrumented enzyme immunoassay and other techniques (Kupferberg, 1978; Jolley et aL, 1981; Schottelius, 1978; Zuk et al., 1985). Chromatographic methods allow simultaneous determination of multiple drug levels and may be somewhat more accurate for research purposes, but the immunoassays are more convenient, cheaper and more widely used clinically. For practical purposes, there is excellent correlation among the various methods (Cochran et al., 199 I; Thomas et al., 1991). Drug levels and 'therapeutic ranges' must be interpreted in light of the clinical studies that have been done to establish them. Unfortunately, many of these studies have suffered from design flaws, such as lack of blinding or appropriate controls, which complicate their interpretation. Study design can have an important effect on results. If a cross-over is used, for example, an adequate washout period must be allowed between treatment arms to eliminate carryover effects. The clinical measures used to assess the relevance of blood levels must be defined carefully. These can include seizure frequency, toxicity scores, or other variables. Small variations in these factors, such as adjusting the range of 'low', 'medium' or 'high' seizure frequency can, depending on their distribution in the study population, have a substantial effect on the results. Retrospective analysis of the 'clinical utility' of AED measurements has particular pitfalls. Larkin et al. (1991) found that there was wide variation in physicians' response to AED levels. In an outpatient clinic setting, for example, only 29% of levels above the therapeutic range were followed by a change in regimen and in 20% of these cases, the dose was raised. The seizure type and epilepsy syndrome of the patients in the study are important, although often ill-defined. A 'therapeutic level' is only meaningful if a drug is effective for the seizures being treated. Carbamazepine (CBZ) has no therapeutic level against primary generalized epilepsy with absence seizures. Results can be confounded by seizure severity as well. If regimens are not fixed, patients with more severe, unresponsive seizures may be given higher doses of drug precisely because they do not respond, leading to the apparently paradoxical result that lower drug levels seem more effective. Even within a particular syndrome such as localization-related epilepsy, intrinsic drug effectiveness against particular seizure types may vary. Schmidt et al. (1986) have suggested that higher drug levels are needed to control partial rather than generalized seizures. In patients being withdrawn from PB, complex partial seizures (CPS) occur in the 15-20 mg/L range, while generalized tonic clonic seizures (GTCS) show an increase when levels fall considerably lower (Figs I and 2) (Theodore et al., 1987). These observations are in accord with clinical experience: many patients with localization-related epilepsy, particularly of temporal lobe origin, continue to have frequent CPS while their GTCS are well-controlled.
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FIG. 1. Seizures during phenobarbital withdrawal. A statistically significant increase, compared to both higher and lower plasma concentration, occurred when patients PB blood levels were passing through the 15-20 mg/L range. Reprinted from Theodore et al. (1987).
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FIG. 2. In a patient being withdrawn from phenobarbital, complex partial seizures peaked when PB level was 20, while GTCS did not occur until level was below 5. Reprinted from Theodore et al. (1987).
Pharmacokinetic as well as pharmacodynamic factors play a role in the evaluation of clinical reports of the relation of AED levels to clinical toxicity. Levels of potentially neuroactive but unmeasured or even unidentified metabolites, protein binding and the time at which levels were drawn in relation to dosing and clinical evaluation must all be taken into account. Often, this information is not available. It is particularly difficult to evaluate the relation of drug levels to clinical effect in studies that include patients taking more than one drug. Considering all these factors, the degree to which AED levels have been shown to correlate with clinical effect is surprising (Manon-Espaillat et aL, 1991). A review of the data for several drugs in current use will put the difficulty of clinical interpretation of drug levels in perspective. There are too few data on newer and experimental AEDs to draw reasonable conclusions on the clinical use of their levels (Theodore et al., 1991).
2. PHENOBARBITAL The broad therapeutic range of 10-40 mg/L often quoted for PB is not of much clinical value. Several studies have suggested that GTCS can be controlled with levels of approximately 10 mg/L, but that higher levels are needed for patients with CPS (Buchthal et al., 1968; Feely et al., 1980; Schmidt et al., 1986; Theodore et al., 1987). On the other hand, the value of levels above 25 mg/L has never been conclusively demonstrated (Painter, 1989; Mattson and Cramer, 1989). In infants, there may be a lower brain to plasma concentration ratio and a clinical response is unusual with levels less than 16 mg/L (Painter et al., 1981). The point at which clinically apparent drug toxicity occurs is equally ill-defined. Buchthal and Svensmark found no evidence of PB toxicity with levels below 20 mg/L (Buchthal and Svensmark, 1959-1960). Patients with surprisingly high levels report no side effects. Plaa and Hine (1960) found that of 61 patients on PB, only 4 had slowness and ataxia, with a range of levels from 36-77 mg/L. Tolerance develops to the sedative effects of PB. On initial therapy, patients can complain of sedation when the level is only 5 mg/L; this disappears over time even with rising levels (Butler et al., 1954). Thirty-three percent of patients in a double blind study complained of sedation when levels were at a mean of 18 mg/L; the number declined to 24% (p < 0.04) after several weeks even though levels rose to 24 mg/L (Mattson and Cramer, 1989). Patients with levels as high as 77 mg/L can be alert; the range of levels in patients who were comatose but had preserved deep tendon reflexes was 65-117 mg/L (Sunshine, 1957). On routine clinical evaluation, PB is a very well tolerated drug. However, neuropsychological side effects of AEDs, and particularly sedative-hypnotic drugs, may occur even when overt sedation or clinical signs are absent (Theodore and Porter, 1983). Although the frequency of behavioral and neuropsychological toxicity in patients taking PB may be related in part to other factors, there is a significant inverse relation between PB levels and neuropsychological performance (Painter, 1989; J~T S 4 / ~ - - F
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Meador et al., 1990). Wolf and Forsythe (1978) found that behavior disturbances, frequently found in children taking PB were not related to drug levels, but the study may have been confounded by pre-existing behavior disorders, which were highly correlated with an adverse drug response (Wolf and Forsythe, 1978). It is more difficult to establish therapeutic ranges for primidone (PRM), which is metabolized to PB and phenylethylmalonamide. Data from the Veteran's Administration Cooperative Study suggests that an optimal range when primidone is used as monotherapy may be 10-15, with PB levels about 15 (Mattson and Cramer, 1989). PRM was the least well tolerated drug among the four used in that study, primarily for reasons of toxicity (Mattson et al., 1985).
3. PHENYTOIN Buchthal and Svensmark (1959-1960), in a landmark investigation, studied the relation of serum PHT levels to clinical effect. The lowest level at which they thought efficacy occurred was 10 mg/L, but many of their patients had levels ranging up to 50 mg/L and improvement seemed more likely with levels above 15 mg/L (Buchthal and Svensmark, 1959-1960). In ambulatory patients with generalized tonic clonic seizures, greater improvement was found when PHT levels were in the 15-20 mg/L than 10-15 mg/L range (Buchthal et al., 1960). Schmidt et al. (1986) found that patients with GTCS alone were well-controlled at a mean PHT level of 14 mg/L and patients with CPS at a mean level of 23 mg/L. Higher initial levels may be needed to control patients in status than for maintenance therapy (Buchthal and Svensmark, 1959-1960). In a more recent study, however, no difference in levels was found between patients who did not stop seizing after i.v. PHT and those who did (Leppik et al., 1983). The main predictor of outcome was etiology. However, mean plasma level in both patient groups was above 25 mg/L at 30 min after infusion. The range of serum concentrations at which PHT toxicity occurs is broad, but clear general patterns have been found. Above 20 mg/L, nystagmus occurs on lateral gaze and dystaxia may be found on neurologic exam. Above 30 mg/L, obvious gait ataxia is often present and above 40 mg/L, spontaneous nystagmus, as well as more profound disorders of eye movements and lethargy are apparent (Kutt et al., 1964). Some investigators have reported few signs of toxicity at levels below 25 mg/L, while others have reported mild side effects such as nystagmus on far lateral gaze with levels in the 10-15 mg/L range (Stensrud and Palmer, 1964; Kutt et al., 1964; Haerer and Grace, 1969). Buchthal and Svensmark found that acute neurologic side effects such as ataxia and nystagmus did not occur in their patients with levels below 14 mg/L; in the range 15-29 mg/L only 15% complained of toxicity and in the range 30-60 mg/L 26% had none, 24% mild and 50% severe toxicity (Buchthal and Svensmark, 1959-1960; Buchthal et al., 1960). In a study of 110 patients taking PHT, Triedman et al. (1960) found that all 19 with ataxia or lethargy had blood levels above 30 mg/L, while of 91 nontoxic patients, 13 had levels above 30 mg/L and 1 above 50 mg/L. Neurologic side effects were associated with significantly higher PHT levels (13.4 + 5.5 vs 18.4 + 8.2 mg/L) in a study by Herranz et al. (1988). The importance of blood levels in evaluating PHT toxicity was underlined by a recent reanalysis of a study which had originally been interpreted as showing greater adverse neuropsychological side effects of PHT than CBZ. When patients with high drug levels were eliminated, there was no difference between PHT and CBZ effects (Dodrill and Troupin, 1991). Nevertheless, the range of blood levels at which patients either achieve seizure control or experience drug toxicity is very broad. Schumacher et al. (1991) performed a retrospective analysis of the relation between serum PHT concentration and a number of clinical response measures among patients who had participated in a blinded trial of PHT monotherapy. Although there were positive correlations between levels and clinical indices, none of the relationships were statistically significant. Test sensitivity, specificity and predictive value were all low. Theoretically, only free drug is able to reach receptor sites. PHT is 90% bound to plasma protein and it has been suggested that measuring free levels may be valuable. PHT free fraction is altered in a number of pathological conditions such as renal disease, in the elderly (due to lower serum albumin), it increases during the last trimester of pregnancy and is affected by interactions with other
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AEDs, particularly valproic acid (VPA) (Theodore, 1987). Booker and Darcy (1973) reported a closer correlation of drug toxicity with free than total PHT measurements, but their patients were taking other drugs in addition to PHT, making the study more difficult to interpret. The range of free levels at which patients experience toxicity is, as for total levels, very broad (Lesser et al., 1984). In a study of outpatients with normal renal function, free PHT showed a slightly better correlation (R = 0.59) than total PHT (R = 0.49) with toxicity score determined by a blind rater (Theodore et al., 1985). Alterations in seizure frequency have not convincingly been related to changes in free levels (Wilder et al., 1976; Lesser et al., 1984; Theodore et al., 1985). Therapeutic norms for unbound plasma AED levels are even less well established than those for total levels. Free PHT measurements are probably not needed in routine practice, but may be helpful when alterations of normal binding are anticipated, or toxicity seems greater than expected on the basis of total drug level.
4. CARBAMAZEPINE The shorter half-life of CBZ compared to PB and PHT makes it more difficult to determine therapeutic ranges for the drug, as marked fluctuations occur throughout the day even in patients taking three or four doses. It may be difficult, however, to demonstrate clinical effects of CBZ fluctuations even with sophisticated testing. A mean fluctuation of 38% had no effect on a battery of tests of reaction time, memory, attention and motor performance (Reinvang et al., 1991). Similar studies of controlled release CBZ formulations failed to show a strong relation between blood levels and drug toxicity (Aldenkamp et al., 1987). Not all studies used appropriate controls for the timing of drug level measurement in relation to symptoms and signs of toxicity. Although most investigators have reported effective ranges of 4-12 mg/L, many patients tolerate much higher levels without toxicity (Kutt et al., 1975; Monaco et al., 1976; Simonsen et al., 1976; Troupin et al., 1977). CBZ has an active metabolite, carbamazepine 10,1 l-epoxide (CBZ-E), which may contribute to the therapeutic effect of the drug (Eichelbaum et al., 1976). CBZ metabolism is usually increased by coadministration of other AEDs and the CBZ-E/CBZ ratio increases (Brodie et al., 1983; Theodore et al., 1989). Measurement of CBZ-E, however, has not been shown to be clinically useful (Theodore et al., 1989). CBZ has less protein binding than PHT and is less likely to have relevant free level effects (Theodore, 1987). No convincing relation between CBZ free levels and toxicity or seizure control has been demonstrated (Lesser et al., 1984).
5. VALPROIC ACID Most studies have found a consistent therapeutic VPA effect against primary generalized absence seizures with trough levels in the 50-100 mg/L range, although some investigators have reported good results at lower levels (Villareal et al., 1978; Sato et al., 1982; Covanis et al., 1982; Farrell et al., 1986). The difference in results may be due in part to the use of video-EEG monitoring and thus more accurate seizure detection, in some studies (Sato et al., 1982). An interesting delay in clinical effect after high blood levels, as reported in some studies, has been linked to the putative effect on GABA levels in the brain (Henricksen and Johannessen, 1982). VPA has been used for other seizure types. A mean trough level of 57 mg/L was as effective as a PHT level of 12.6 mg/L in preventing GTCS (Wilder et al., 1983). In a double-blind trial, VPA was significantly less effective than CBZ for treatment of CPS (although AED levels were not included in the preliminary report of the study) and it would be inappropriate to apply the therapeutic range for patients with primary generalized epilepsy to this very different patient group (Mattson et al., 1991). Patients with atonic or 'atypical absence' seizures respond poorly to most AEDs, although VPA may be the most effective; many investigators feel that plasma levels up to 125 mg/L should be attained in these children. The clinical pharmacology of VPA complicates interpretation of blood levels. In normal adults, VPA is 87-95% bound to plasma protein; free fraction increases with increasing plasma level and may be twice as high at 100 mg/L than at 50 mg/L (Riva et al., 1983; Bowdle et al., 1980).
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Physiologic alterations in plasma lipids may affect VPA binding. In patients with renal disease, the unbound fraction may be increased to 20--25% despite normal albumin levels (Gugler and Mueller, 1978). PHT at 20 mg/mL increased free fraction in vitro from 6 to 12% (Cramer and Mattson, 1979). The fluctuations in VPA binding are much greater than for PHT or CBZ and VPA free levels are more difficult to predict from total levels. Nevertheless, no clear relation between free levels and clinical effect has been established and there is no obvious reason to monitor free rather than total drug levels (Froscher et al., 1985; Barre et al., 1988). VPA, like CBZ, shows fairly marked fluctuations in serum levels over the course of a day. Multiple dosing is needed to obtain steady plasma levels. Moreover, a single level, even at morning trough, may not provide enough information to make clinical decisions. VPA toxicity, especially sedation and alteration of consciousness, does appear to be more common at levels over 100 mg/L, although clinical variation is wide (Chadwick, 1985). A recent study found that children without any side effects had a mean level of 60.7 + 17.5 mg/L, while those with drowsiness had a level of 88 + 36.9 mg/L (Herranz et al., 1988).
6. CONCLUSION The primary use of AED levels is to help determine if the patient is protected adequately against seizures. All other roles, such as investigations of compliance, drug absorption, metabolism, protein binding and interactions are naturally subsidary to and part of, this goal (Fig. 3). In the pre-AED era, Yahr et al. (1952) suggested that AED therapy should be taken to toxicity before a drug is given up and it is clear that patients may tolerate levels of AEDs, particularly PHT and CBZ, considerably beyond the 'therapeutic range' (Lesser et al., 1984; Schmidt, 1983). If a patient is seizure-free on an AED dose which does not produce any overt side effects, why should levels be measured? Clinical drug toxicity usually can be detected by the examining physician, but an important role of AED levels is to help assess risk for more subtle drug effects, particularly neuropsychological impairment, that may not be apparent on clinical examination. An increasing body of evidence suggests that all drugs have such adverse effects and their incidence is related to blood levels (Dodrill and Troupin, 1991). AED levels will help patient and physician to assess the 'cost' of having a CBZ level of 15 mg/L or PHT level of 30 mg/L. One of the most important factors in interpreting AED levels is the time after dosing at which they were drawn. This is particularly true for short half-life drugs such as CBZ and VPA. Levels drawn at different times can be used for different therapeutic judgements: trough to assess seizure
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Rational use of antiepileptic drug levels
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protection; peak to help evaluate signs or symptoms of possible drug toxicity. Ideally, several levels should be obtained throughout the course of the day, particularly for short half-life drugs such as CBZ and VPA. Blood levels are clearly indicated when patients report seizures. Obviously, it is important to know whether reasonable blood levels are being obtained from one drug before adding a second or trying another. In these patients it may be more useful to obtain several levels over the course of a day than a single measurement, particularly if side effects or seizures tend to occur at certain times. In addition, simple partial seizures may cause symptoms such as dizziness which could also be due to drug toxicity and levels may help to distingush between the two. Periodic measurement of levels in well-controlled patients is also necessary to assess compliance, which may decrease over time. Woo et al. 0988) suggested that it is not necessary to raise the doses of seizure-free patients with 'subtherapeutic' levels. It is useful to know, however, whether patients are still taking the drugs, or if changes in absorption, for example, have occurred. If levels have been low all along, drugs may be less likely to be needed at all. AED levels are not the only data upon which clinical decisions are based. Other factors, such as seizure frequency or physicians' judgement of drug toxicity, are important. Nevertheless, they may lead to therapeutic interventions in a significant number of patients (Larkin et aL, 1991). No one has ever pretended that attaining therapeutic levels is an end in itself. Like any clinical test, AED levels should be obtained to answer a specific question. Formulating a question includes deciding whether the laboratory test to be ordered has a reasonable chance of answering it. A rational approach to the use of AED levels includes understanding that therapeutic ranges are a guide which has to be used in the appropriate clinical context. It may be preferable to perform well-planned investigations during which several levels are obtained in selected patients, than routine measurements in a large clinic population.
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F. and The VA Epilepsy Cooperative Study # 264 Group (1991) Comparison between carbamazepine and valproate for complex partial and secondarily generalized tonic clonic seizures. Epilepsia 32 (Suppl. 3): 18. MEADOR, K. J., LORING, D. W., HUH, K., GALLAGHER,B. B. and KING, D. W. (1990) Comparative cognitive effects of anticonvulsants. Neurology 40: 391-394. MONACO, A., RICClO, A., BENNA, P., COVAC1CH,A., DURELLI, L., FANTIN, M., FURLAN, P. M., GILLI, M., MUTANI, R., TRONI, W., GERNA, M. and MORSELLI,P. L. (1976) Further observations on carbamazepine plasma levels in epileptic patients. Neurology 26: 936-943. MOURADIAN, M. M., JUNCOS,J. L., FABBRINI,G. and CHASE,T. N. (1987) Motor fluctuations in Parkinson's Disease: pathogenetic and therapeutic studies. Ann. Neurol. 22: 475-479. PAINTER,M. J. (1989) Phenobarbital: clinical use. In: Antiepileptic Drugs, pp. 329-340, LEVY, R. H., DREIFUSS, F. E., MATTSON R. H., MELDRUM B. S. and PENRY, J. K. (eds) Raven Press, New York. PAINTER,M. J., PIPPENGER,C. E., WASTERLAIN,C., BARMADA,M., PITLICK,W., CARTER,G. and ABERN,S. (1981) Phenobarbital and phenytoin in neonatal seizures: metabolism and tissue distribution. Neurology 31: 1107-1112. PLAA, G. L. and HINE, C. H. (1956) A method for the simultaneous determination of phenobarbital and diphenyhydantoin in blood. J. Lab. clin. Med. 47: 649-657. PLAA, G. L. and HINE, C. H. (1960) Hydantoin and barbiturate blood levels observed in epileptics. Arch. Int. Pharmaeodyn. Ther. 128: 375-382. REINVANG,I., BJARVEIT,S., JOHANNESSEN,S. I., HAGEN, O. P., LARSEN,S., FAGERTHUN,H. and GJERSTAD, L. (1991) Cognitive function and time of day variation in serum carbamazepine concentration in epileptic patients treated with monotherapy. Epilepsia 32:116-121. RIVA, R., ALBAN1,F., CORTELLI,P., GOBBI,G., PERUCCA,E. and BARUZZI,A. (1983) Diurnal fluctuations in free
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SATO,S., WHITE,B. G., PENRY,J. K. DREXFUSS,F. E., SACKELLARES,J. C. and KtJPFERBERG,H. J. (1982) Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 32: 157-163. SCHMIDT,D. (1983) Reduction of two drug therapy in intractable epilepsy. Epilepsia 24: 368-376. SCHMIDT, D., EINICKE,I. and HAENSEL,F. (1986) The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital and carbamazepine. Arch. Neurol. 43: 263-265. SCHOTTEUUS,D. D. (1978) Homogeneous immunassay system (EMIT) for quantitation of antiepileptic drugs in biological fluids. In: Antiepileptic Drugs: Quantitative Analysis and Interpretation, pp. 95-108, PIPPENGER, C. E., PENRV, J. K. and KUTT, H. (eds) Raven Press, New York. SCHUMACHER,G. E., BARR,J. T., BROWNE,T. R., COLLINS,J. F. and The VA Epilepsy Cooperative Study Group (1991) Test performance characteristics of the serum phenytoin concentration (SPC): the relationship between SPC and patient response. Ther. Drug Monitor. 13: 318-324. SIMONSEN,N., OLSEN, I. Z., KUHL, V., LUND, M. and WENDELBOE,J. (1976) A comparative controlled study between carbamazepine and diphenylhydantoin in psychomotor epilepsy. Epilepsia 17: 169-76. STENSRUD,P. A. and PALMER,H. (1964) Serum phenytoin determinations in epileptics. Epilepsia 5: 364-370. SUNSHINE,I. (1957) Chemical evidence of tolerance to phenobarbital. J. Lab. clin. Med. 50: 127-133. SVENSMARK,O. and KRISTENSEN,P. (1963) Determination of diphenylhydantoin and phenobarbital in small amounts of serum. J. Lab. clin. Med. 61: 501-507. SVENSMARK,O., SCHILLER,P. J. and BUCHTAL,F. (1960) 5,5-diphenylhydantoin (Dilantin) blood levels after oral or intravenous dosage in man. Acta Pharmac. Toxic. 16: 331-336. THEODORE,W. H. (1987) Should we measure free antiepileptic drug levels? Clin. Neuropharmac. 10: 26-37. THEODORE,W. H. and PORTER,R. J. (1983) Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann. NeuroL 13: 320-324. THEODORE,W. n., Yu, L., PRICE,B., YONEKAWA,W., PORTER,R. J., KAPETANOVIK,I., MOORE,H. and KUPFERBERG,H. J. (1985) The clinical value of free phenytoin levels. Ann. Neurol. 18: 90-93. THEODORE,W. H., PORTER,R. J. and RAUBERTAS,R. F. (1987) Seizures during barbiturate withdrawal: relation to blood level. Ann. Neurol. 22: 644-647. THEODORE,W. H., NARANG,P. K., HOLMES,M. D., REEVES,P. and NICE, F. J. (1989) Carbamazepine and its epoxide: relation of plasma levels to toxicity and clinical control. Ann. Neurol. 25: 194-196. THEODORE,W. H., RAUBERTAS,R. F., PORTER,R. J., NICE, F., DEVINSKY,O., REEVES,P., BROMFIELD,E., ITO, B. and BALISH,M. (1991) Felbamate: a clinical trial for complex partial seizures. Epilepsia 32: 392-397. THOMAS,K. C., HULLIN,D. A. and DAVIS,S. J. (1991) Comparison of enzyme immunoassay and fluorescence polarization immunoassay as techniques for measuring anticonvulsant drugs on the same analytical instrument. Ther. Drug Monitor. 13: 172-176. TRIEDMAN,H. M., FISHMAN,R. A. and YAHR, M. D. (1960) Determination of plasma and cerebrospinal fluid levels of dilantin in the human. Trans. Am. Neurol. Ass. 85: 166-170. TROUPIN, A. S., OJEMANN, L. M., HALPERN, L., DODRILL, C., WILKUS, R., FRIEL, P. and FEIGL, P. (1977) Carbamazepine--a double-blind comparison with phenytoin. Neurology 27: 511-519. VILLAREAL,H. J., WILDER,B. J., WILLMORE,L. J. BAUMANN,A. W., HAMMOND,E. J. and BRUNI,J. (1978) Effect of valproic acid on spike and wave discharges in patients with absence seizures. Neurology 28: 886-891. WILDER, B. J., WILLMORE,L. J., BRUNI,J. and VILLAREAL,H. J. (1976) Valproic acid: interaction with other anticonvulsant drugs. Neurology 28: 892-896. WILDER, B. J., RAMSEY,R. E., MURPHY, J. V., KARAS, B. J., MARQUARDT,K. and HAMMOND,E. J. (1983) Comparison of valproic acid and phenytoin in newly diagnosed tonic-clonic seizures. Neurology 33: 1474-1476. WOLF,S. and FORSYTHE,A. (1978) Behavior disturbance, phenobarbital and febrile seizures. Pediatrics 61: 728-731. WOO, E., CHAN,Y. M., Yu, Y. L., CHAN,Y. W. and HUANG,C. Y. (1988) If a well-stabilized epileptic patient has a subtherapeutic antiepileptic drug level, should the dose be increased? A randomized prospective study. Epilepsia 29: 129-139. YAHR, M. D., SCIARRA,D., CARTER,S. and MERRITT,H. H. (1952) Evaluation of standard anticonvuslant therapy in 319 patients J. Am. Med. Ass. 150: 663-667. ZUK, R. F., GINSBERG,V. K., HOUTS,T., RABBLE,J., MERRICK,H., ULLMAN,E. F., FISCHER,M. M., SIZTO,C. C., STISO,S. N. and LITMAN,D. J. (1985) Enzyme immunochromatography--a quantitative immunoassay requiring no instrumentation. Clin. Chem. 31:1144-1150.
0163-7258/92$15.00 1992PergamonPressLtd
Associate Editor: M. J. BRODIE
R A T I O N A L USE OF ANTIEPILEPTIC D R U G LEVELS WILLIAM H. THEODORE Clinical Epilepsy Section, National Institutes of Health, Bethesda MD 20892, U.S.A.
Abstraet--Antiepileptic drug (AED) levels are obtained frequently in clinical practice, but their complex relation to seizures or drug toxicity often makes interpretation of the results difficult. Research studies have not always taken into account clinical, as well as pharmacokinetic and pharmacodynamic, factors which may influence the drug level-effect relationship. AED levels should be drawn at an appropriate time in relation to drug ingestion and clinical symptoms. Systematic investigations in selected patients, during which several levels are obtained, may be more rewarding than routine measurements in a large clinic population.
CONTENTS 1. Introduction 2. Phenobarbital 3. Phenytoin 4. Carbamazepine 5. Valproic Acid 6. Conclusion References
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1. I N T R O D U C T I O N The unique role of antiepileptic drug (AED) level measurements in clinical management is dictated by the peculiarly intermittant nature of seizure disorders. Patients with seizures may go for weeks or months without any symptoms against which drug effects can be judged. Moreover (except in the case of children with absence), physicians treating patients with epilepsy tend not to see seizures occur and the neurological examination usually is normal. Clinical signs or symptoms of drug toxicity, such as diplopia or nystagrnus, may be intermittant. Thus, few objective (at least to the physician) measures of drug effect are available. In contrast, in patients with myasthenia gravis or Parkinson's Disease, the clinical effects of the drugs are usually obvious within several hours of dosing. The role of drug levels in conditions such as Parkinson's Disease is being increasingly recognized, but remains far less prominant than in epilepsy (Mouradian et al., 1987). Clinical measurement of AED levels became practical in the late 1950s when spectrophotometric and colorimetric assays for phenytoin (PHT) were developed (Plaa and Hine, 1956; Dill et al., 1956). These methods were sensitive to interference by phenobarbital (PB), a particularly important consideration when many patients were taking both drugs simultaneously and further modifications were devised to separate the two drugs (Glazko, 1972). An improved method designed to measure both P H T and PB in blood simultaneously was devised by Svensmark and associates and used in several important early studies of the relation of drug levels to clinical efficacy (Svensmark et al., 1960; Svensmark and Kristensen, 1963). Abbreviations--AED, antiepileptic drug; CBZ, carbamazepine; CBZ-E, carbamazepine 10,11-epoxide; CPS, complex partial seizures; GTCS, generalized tonic clonic seizures; PB, phenobarbital; PHT, phenytoin; PRM, primidone; VPA, valproic acid.
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Subsequent methods included gas and then high pressure liquid chromatography, followed by enzyme multiplied immunochemical assay (EMIT), fluorescence polarization immunoassay, noninstrumented enzyme immunoassay and other techniques (Kupferberg, 1978; Jolley et aL, 1981; Schottelius, 1978; Zuk et al., 1985). Chromatographic methods allow simultaneous determination of multiple drug levels and may be somewhat more accurate for research purposes, but the immunoassays are more convenient, cheaper and more widely used clinically. For practical purposes, there is excellent correlation among the various methods (Cochran et al., 199 I; Thomas et al., 1991). Drug levels and 'therapeutic ranges' must be interpreted in light of the clinical studies that have been done to establish them. Unfortunately, many of these studies have suffered from design flaws, such as lack of blinding or appropriate controls, which complicate their interpretation. Study design can have an important effect on results. If a cross-over is used, for example, an adequate washout period must be allowed between treatment arms to eliminate carryover effects. The clinical measures used to assess the relevance of blood levels must be defined carefully. These can include seizure frequency, toxicity scores, or other variables. Small variations in these factors, such as adjusting the range of 'low', 'medium' or 'high' seizure frequency can, depending on their distribution in the study population, have a substantial effect on the results. Retrospective analysis of the 'clinical utility' of AED measurements has particular pitfalls. Larkin et al. (1991) found that there was wide variation in physicians' response to AED levels. In an outpatient clinic setting, for example, only 29% of levels above the therapeutic range were followed by a change in regimen and in 20% of these cases, the dose was raised. The seizure type and epilepsy syndrome of the patients in the study are important, although often ill-defined. A 'therapeutic level' is only meaningful if a drug is effective for the seizures being treated. Carbamazepine (CBZ) has no therapeutic level against primary generalized epilepsy with absence seizures. Results can be confounded by seizure severity as well. If regimens are not fixed, patients with more severe, unresponsive seizures may be given higher doses of drug precisely because they do not respond, leading to the apparently paradoxical result that lower drug levels seem more effective. Even within a particular syndrome such as localization-related epilepsy, intrinsic drug effectiveness against particular seizure types may vary. Schmidt et al. (1986) have suggested that higher drug levels are needed to control partial rather than generalized seizures. In patients being withdrawn from PB, complex partial seizures (CPS) occur in the 15-20 mg/L range, while generalized tonic clonic seizures (GTCS) show an increase when levels fall considerably lower (Figs I and 2) (Theodore et al., 1987). These observations are in accord with clinical experience: many patients with localization-related epilepsy, particularly of temporal lobe origin, continue to have frequent CPS while their GTCS are well-controlled.
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FIG. 1. Seizures during phenobarbital withdrawal. A statistically significant increase, compared to both higher and lower plasma concentration, occurred when patients PB blood levels were passing through the 15-20 mg/L range. Reprinted from Theodore et al. (1987).
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FIG. 2. In a patient being withdrawn from phenobarbital, complex partial seizures peaked when PB level was 20, while GTCS did not occur until level was below 5. Reprinted from Theodore et al. (1987).
Pharmacokinetic as well as pharmacodynamic factors play a role in the evaluation of clinical reports of the relation of AED levels to clinical toxicity. Levels of potentially neuroactive but unmeasured or even unidentified metabolites, protein binding and the time at which levels were drawn in relation to dosing and clinical evaluation must all be taken into account. Often, this information is not available. It is particularly difficult to evaluate the relation of drug levels to clinical effect in studies that include patients taking more than one drug. Considering all these factors, the degree to which AED levels have been shown to correlate with clinical effect is surprising (Manon-Espaillat et aL, 1991). A review of the data for several drugs in current use will put the difficulty of clinical interpretation of drug levels in perspective. There are too few data on newer and experimental AEDs to draw reasonable conclusions on the clinical use of their levels (Theodore et al., 1991).
2. PHENOBARBITAL The broad therapeutic range of 10-40 mg/L often quoted for PB is not of much clinical value. Several studies have suggested that GTCS can be controlled with levels of approximately 10 mg/L, but that higher levels are needed for patients with CPS (Buchthal et al., 1968; Feely et al., 1980; Schmidt et al., 1986; Theodore et al., 1987). On the other hand, the value of levels above 25 mg/L has never been conclusively demonstrated (Painter, 1989; Mattson and Cramer, 1989). In infants, there may be a lower brain to plasma concentration ratio and a clinical response is unusual with levels less than 16 mg/L (Painter et al., 1981). The point at which clinically apparent drug toxicity occurs is equally ill-defined. Buchthal and Svensmark found no evidence of PB toxicity with levels below 20 mg/L (Buchthal and Svensmark, 1959-1960). Patients with surprisingly high levels report no side effects. Plaa and Hine (1960) found that of 61 patients on PB, only 4 had slowness and ataxia, with a range of levels from 36-77 mg/L. Tolerance develops to the sedative effects of PB. On initial therapy, patients can complain of sedation when the level is only 5 mg/L; this disappears over time even with rising levels (Butler et al., 1954). Thirty-three percent of patients in a double blind study complained of sedation when levels were at a mean of 18 mg/L; the number declined to 24% (p < 0.04) after several weeks even though levels rose to 24 mg/L (Mattson and Cramer, 1989). Patients with levels as high as 77 mg/L can be alert; the range of levels in patients who were comatose but had preserved deep tendon reflexes was 65-117 mg/L (Sunshine, 1957). On routine clinical evaluation, PB is a very well tolerated drug. However, neuropsychological side effects of AEDs, and particularly sedative-hypnotic drugs, may occur even when overt sedation or clinical signs are absent (Theodore and Porter, 1983). Although the frequency of behavioral and neuropsychological toxicity in patients taking PB may be related in part to other factors, there is a significant inverse relation between PB levels and neuropsychological performance (Painter, 1989; J~T S 4 / ~ - - F
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Meador et al., 1990). Wolf and Forsythe (1978) found that behavior disturbances, frequently found in children taking PB were not related to drug levels, but the study may have been confounded by pre-existing behavior disorders, which were highly correlated with an adverse drug response (Wolf and Forsythe, 1978). It is more difficult to establish therapeutic ranges for primidone (PRM), which is metabolized to PB and phenylethylmalonamide. Data from the Veteran's Administration Cooperative Study suggests that an optimal range when primidone is used as monotherapy may be 10-15, with PB levels about 15 (Mattson and Cramer, 1989). PRM was the least well tolerated drug among the four used in that study, primarily for reasons of toxicity (Mattson et al., 1985).
3. PHENYTOIN Buchthal and Svensmark (1959-1960), in a landmark investigation, studied the relation of serum PHT levels to clinical effect. The lowest level at which they thought efficacy occurred was 10 mg/L, but many of their patients had levels ranging up to 50 mg/L and improvement seemed more likely with levels above 15 mg/L (Buchthal and Svensmark, 1959-1960). In ambulatory patients with generalized tonic clonic seizures, greater improvement was found when PHT levels were in the 15-20 mg/L than 10-15 mg/L range (Buchthal et al., 1960). Schmidt et al. (1986) found that patients with GTCS alone were well-controlled at a mean PHT level of 14 mg/L and patients with CPS at a mean level of 23 mg/L. Higher initial levels may be needed to control patients in status than for maintenance therapy (Buchthal and Svensmark, 1959-1960). In a more recent study, however, no difference in levels was found between patients who did not stop seizing after i.v. PHT and those who did (Leppik et al., 1983). The main predictor of outcome was etiology. However, mean plasma level in both patient groups was above 25 mg/L at 30 min after infusion. The range of serum concentrations at which PHT toxicity occurs is broad, but clear general patterns have been found. Above 20 mg/L, nystagmus occurs on lateral gaze and dystaxia may be found on neurologic exam. Above 30 mg/L, obvious gait ataxia is often present and above 40 mg/L, spontaneous nystagmus, as well as more profound disorders of eye movements and lethargy are apparent (Kutt et al., 1964). Some investigators have reported few signs of toxicity at levels below 25 mg/L, while others have reported mild side effects such as nystagmus on far lateral gaze with levels in the 10-15 mg/L range (Stensrud and Palmer, 1964; Kutt et al., 1964; Haerer and Grace, 1969). Buchthal and Svensmark found that acute neurologic side effects such as ataxia and nystagmus did not occur in their patients with levels below 14 mg/L; in the range 15-29 mg/L only 15% complained of toxicity and in the range 30-60 mg/L 26% had none, 24% mild and 50% severe toxicity (Buchthal and Svensmark, 1959-1960; Buchthal et al., 1960). In a study of 110 patients taking PHT, Triedman et al. (1960) found that all 19 with ataxia or lethargy had blood levels above 30 mg/L, while of 91 nontoxic patients, 13 had levels above 30 mg/L and 1 above 50 mg/L. Neurologic side effects were associated with significantly higher PHT levels (13.4 + 5.5 vs 18.4 + 8.2 mg/L) in a study by Herranz et al. (1988). The importance of blood levels in evaluating PHT toxicity was underlined by a recent reanalysis of a study which had originally been interpreted as showing greater adverse neuropsychological side effects of PHT than CBZ. When patients with high drug levels were eliminated, there was no difference between PHT and CBZ effects (Dodrill and Troupin, 1991). Nevertheless, the range of blood levels at which patients either achieve seizure control or experience drug toxicity is very broad. Schumacher et al. (1991) performed a retrospective analysis of the relation between serum PHT concentration and a number of clinical response measures among patients who had participated in a blinded trial of PHT monotherapy. Although there were positive correlations between levels and clinical indices, none of the relationships were statistically significant. Test sensitivity, specificity and predictive value were all low. Theoretically, only free drug is able to reach receptor sites. PHT is 90% bound to plasma protein and it has been suggested that measuring free levels may be valuable. PHT free fraction is altered in a number of pathological conditions such as renal disease, in the elderly (due to lower serum albumin), it increases during the last trimester of pregnancy and is affected by interactions with other
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AEDs, particularly valproic acid (VPA) (Theodore, 1987). Booker and Darcy (1973) reported a closer correlation of drug toxicity with free than total PHT measurements, but their patients were taking other drugs in addition to PHT, making the study more difficult to interpret. The range of free levels at which patients experience toxicity is, as for total levels, very broad (Lesser et al., 1984). In a study of outpatients with normal renal function, free PHT showed a slightly better correlation (R = 0.59) than total PHT (R = 0.49) with toxicity score determined by a blind rater (Theodore et al., 1985). Alterations in seizure frequency have not convincingly been related to changes in free levels (Wilder et al., 1976; Lesser et al., 1984; Theodore et al., 1985). Therapeutic norms for unbound plasma AED levels are even less well established than those for total levels. Free PHT measurements are probably not needed in routine practice, but may be helpful when alterations of normal binding are anticipated, or toxicity seems greater than expected on the basis of total drug level.
4. CARBAMAZEPINE The shorter half-life of CBZ compared to PB and PHT makes it more difficult to determine therapeutic ranges for the drug, as marked fluctuations occur throughout the day even in patients taking three or four doses. It may be difficult, however, to demonstrate clinical effects of CBZ fluctuations even with sophisticated testing. A mean fluctuation of 38% had no effect on a battery of tests of reaction time, memory, attention and motor performance (Reinvang et al., 1991). Similar studies of controlled release CBZ formulations failed to show a strong relation between blood levels and drug toxicity (Aldenkamp et al., 1987). Not all studies used appropriate controls for the timing of drug level measurement in relation to symptoms and signs of toxicity. Although most investigators have reported effective ranges of 4-12 mg/L, many patients tolerate much higher levels without toxicity (Kutt et al., 1975; Monaco et al., 1976; Simonsen et al., 1976; Troupin et al., 1977). CBZ has an active metabolite, carbamazepine 10,1 l-epoxide (CBZ-E), which may contribute to the therapeutic effect of the drug (Eichelbaum et al., 1976). CBZ metabolism is usually increased by coadministration of other AEDs and the CBZ-E/CBZ ratio increases (Brodie et al., 1983; Theodore et al., 1989). Measurement of CBZ-E, however, has not been shown to be clinically useful (Theodore et al., 1989). CBZ has less protein binding than PHT and is less likely to have relevant free level effects (Theodore, 1987). No convincing relation between CBZ free levels and toxicity or seizure control has been demonstrated (Lesser et al., 1984).
5. VALPROIC ACID Most studies have found a consistent therapeutic VPA effect against primary generalized absence seizures with trough levels in the 50-100 mg/L range, although some investigators have reported good results at lower levels (Villareal et al., 1978; Sato et al., 1982; Covanis et al., 1982; Farrell et al., 1986). The difference in results may be due in part to the use of video-EEG monitoring and thus more accurate seizure detection, in some studies (Sato et al., 1982). An interesting delay in clinical effect after high blood levels, as reported in some studies, has been linked to the putative effect on GABA levels in the brain (Henricksen and Johannessen, 1982). VPA has been used for other seizure types. A mean trough level of 57 mg/L was as effective as a PHT level of 12.6 mg/L in preventing GTCS (Wilder et al., 1983). In a double-blind trial, VPA was significantly less effective than CBZ for treatment of CPS (although AED levels were not included in the preliminary report of the study) and it would be inappropriate to apply the therapeutic range for patients with primary generalized epilepsy to this very different patient group (Mattson et al., 1991). Patients with atonic or 'atypical absence' seizures respond poorly to most AEDs, although VPA may be the most effective; many investigators feel that plasma levels up to 125 mg/L should be attained in these children. The clinical pharmacology of VPA complicates interpretation of blood levels. In normal adults, VPA is 87-95% bound to plasma protein; free fraction increases with increasing plasma level and may be twice as high at 100 mg/L than at 50 mg/L (Riva et al., 1983; Bowdle et al., 1980).
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Physiologic alterations in plasma lipids may affect VPA binding. In patients with renal disease, the unbound fraction may be increased to 20--25% despite normal albumin levels (Gugler and Mueller, 1978). PHT at 20 mg/mL increased free fraction in vitro from 6 to 12% (Cramer and Mattson, 1979). The fluctuations in VPA binding are much greater than for PHT or CBZ and VPA free levels are more difficult to predict from total levels. Nevertheless, no clear relation between free levels and clinical effect has been established and there is no obvious reason to monitor free rather than total drug levels (Froscher et al., 1985; Barre et al., 1988). VPA, like CBZ, shows fairly marked fluctuations in serum levels over the course of a day. Multiple dosing is needed to obtain steady plasma levels. Moreover, a single level, even at morning trough, may not provide enough information to make clinical decisions. VPA toxicity, especially sedation and alteration of consciousness, does appear to be more common at levels over 100 mg/L, although clinical variation is wide (Chadwick, 1985). A recent study found that children without any side effects had a mean level of 60.7 + 17.5 mg/L, while those with drowsiness had a level of 88 + 36.9 mg/L (Herranz et al., 1988).
6. CONCLUSION The primary use of AED levels is to help determine if the patient is protected adequately against seizures. All other roles, such as investigations of compliance, drug absorption, metabolism, protein binding and interactions are naturally subsidary to and part of, this goal (Fig. 3). In the pre-AED era, Yahr et al. (1952) suggested that AED therapy should be taken to toxicity before a drug is given up and it is clear that patients may tolerate levels of AEDs, particularly PHT and CBZ, considerably beyond the 'therapeutic range' (Lesser et al., 1984; Schmidt, 1983). If a patient is seizure-free on an AED dose which does not produce any overt side effects, why should levels be measured? Clinical drug toxicity usually can be detected by the examining physician, but an important role of AED levels is to help assess risk for more subtle drug effects, particularly neuropsychological impairment, that may not be apparent on clinical examination. An increasing body of evidence suggests that all drugs have such adverse effects and their incidence is related to blood levels (Dodrill and Troupin, 1991). AED levels will help patient and physician to assess the 'cost' of having a CBZ level of 15 mg/L or PHT level of 30 mg/L. One of the most important factors in interpreting AED levels is the time after dosing at which they were drawn. This is particularly true for short half-life drugs such as CBZ and VPA. Levels drawn at different times can be used for different therapeutic judgements: trough to assess seizure
good control ) Persistent~ eizures j
~ /
(toxicity
I
I
msasurs troug~ levels
Clow
/
\
levels
~periodic
~,levels ? )
C
seizure free levels low ,,)
g) stopping dru
) (good levels)
C increase dose )
I
(,.add 2d drug
~
I
consider
)
easure peak nd trough levels
FIG. 3. Suggested scheme for measuring AED levels.
Rational use of antiepileptic drug levels
303
protection; peak to help evaluate signs or symptoms of possible drug toxicity. Ideally, several levels should be obtained throughout the course of the day, particularly for short half-life drugs such as CBZ and VPA. Blood levels are clearly indicated when patients report seizures. Obviously, it is important to know whether reasonable blood levels are being obtained from one drug before adding a second or trying another. In these patients it may be more useful to obtain several levels over the course of a day than a single measurement, particularly if side effects or seizures tend to occur at certain times. In addition, simple partial seizures may cause symptoms such as dizziness which could also be due to drug toxicity and levels may help to distingush between the two. Periodic measurement of levels in well-controlled patients is also necessary to assess compliance, which may decrease over time. Woo et al. 0988) suggested that it is not necessary to raise the doses of seizure-free patients with 'subtherapeutic' levels. It is useful to know, however, whether patients are still taking the drugs, or if changes in absorption, for example, have occurred. If levels have been low all along, drugs may be less likely to be needed at all. AED levels are not the only data upon which clinical decisions are based. Other factors, such as seizure frequency or physicians' judgement of drug toxicity, are important. Nevertheless, they may lead to therapeutic interventions in a significant number of patients (Larkin et aL, 1991). No one has ever pretended that attaining therapeutic levels is an end in itself. Like any clinical test, AED levels should be obtained to answer a specific question. Formulating a question includes deciding whether the laboratory test to be ordered has a reasonable chance of answering it. A rational approach to the use of AED levels includes understanding that therapeutic ranges are a guide which has to be used in the appropriate clinical context. It may be preferable to perform well-planned investigations during which several levels are obtained in selected patients, than routine measurements in a large clinic population.
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