Epilepsin, 32(1):89-95, 1991 Raven Press, Ltd., New York 0 International League Against Epilepsy

Antiepileptic Drug Monitoring at the Epilepsy Clinic: A Prospective Evaluation John G. Larkin, Ariane L. Herrick, *Gerard M. McGuire, *Ian W. Percy-Robb, and Martin J. Brodie Epilepsy Research Unit, University Department of Medicine and Therapeutics, and *Department of Pathological Biochemistry, Western Infirmary, Glasgow, Scotland

Summary: To assess the value of onsite therapeutic drug monitoring at the epilepsy clinic, management decisions were recorded before and immediately after antiepileptic drug (AED) concentrations became available. In the first year of this prospective study, 632 [277 carbamazepine (CBZ), 170 phenytoin (PHT), 113 valproate (VPA), and 72 phenobarbital (PB)] assays were performed during 488 clinic attendances in 182 actively managed epileptic patients. The results of drug analysis led to alterations in management at 114 patient visits, i.e., 23% of those monitored. Dosage was increased in response to the circulating AED concentration in 12% of consultations and decreased in another 7.5%. Unsuspected poor compliance was uncovered in eight patients, and in three others an AED was added or discontinued on the basis of the assay

result. The time of the next appointment was rearranged in 58 attendances. Only 50% of results were in the “therapeutic” ranges for the four major AEDs. Dosage was adjusted (50 up, 16 down) after 54% of low results. “Therapeutic” levels were followed by a change in AED dose (52 up, 31 down) in 26%. Only 29% of concentrations above the “therapeutic” range persuaded the doctor to alter the dosage regimen, and in 20% of these an increase in dose was recommended. On-site AED monitoring had an immediate impact on clinical decisionmaking in >23% of consultations but in a form more subtle than the simple quest for a therapeutic result. Key Words: Anticonvulsants drugs-Therapeutic drug monitoring-CarbamazepinePhenytoin-Valproat+Phenobarbital-Pharmacokinetics.

Tailoring the dose of a drug with the aid of a measured concentration to provide optimum clinical benefit without production of side effects is a seductive concept (Richens and Warrington, 1979; Whiting et al., 1984; Friedman and Greenblatt, 1986). Many pharmacologic properties of antiepileptic drugs (AEDs) support suitability for therapeutic drug monitoring (TDM) (Morselli and Franco-Morselli, 1980; Reynolds, 1980; Eadie, 1984; Brodie, 1985). However, recent worries concerning inappropriate application of results and substantial expense (Beardsley et al., 1983; Bussey and Hoffman, 1983; Brodie et al., 1985; Pitterle et al., 1985; Vozeh, 1987) have prompted the suggestion that monitoring of AEDs may be overused (Chadwick, 1987). The ready availability of AED concentrations encourages the doctor to measure them; this is often coupled with an overoptimistic PerceP-

tion of the relevance of a single assay result (Brodie, 1986; Brodie and Feely, 1988). This can produce unthinking and unnecessary requests for monitoring (Levine et al., 1988) and fuels the tendency to treat the AED concentration rather than the patient [i.e., chasing the “therapeutic” range (Spector et al., 1988)l. Patient pressure may also contribute to the demand for a “blood level.” To assess the effect of an AED concentration on clinical management, an assay service was set up onsite at the epilepsy clinic in the Western Infirmary. A record was made of the physicians’ clinical decisions before and immediately after the result became available. Data from the first 52 weeks of this prospective study are presented. MATERIALS AND METHODS

Patients The epilepsy service at the Western Infirmary in Glasgow is provided by the Clinical Pharmacology Unit. The clinic is staffed by a consultant clinical pharmacologist, a research fcllow , and a medical

Received August 1989; revision accepted December 1989. Address correspondence and reprint requests to Dr. M. J . Brodie at Clinical Pharmacology Unit, University Department of Medicine, Western Infirmary, Glasgow G11 6NT, Scotland.

89

J . G. LARKIN ET AL.

90

registrar. During the year for which data are presented (February 1986 to February 1987), an average of 22 patients attended the clinic each week, four of whom were new referrals. Patients for the study were preselected as requiring active management and were recruited prospectively. Indications for monitoring included poor seizure control, unwelcome polypharmacy , clinical toxicity, suspect compliance, and the introduction of an AED drug. Of 1,162 patient attendances, 42% (488) were monitored during the first year of the study. Six hundred thirty-two drug assays were performed [277 carbamazepine (CBZ), 170 phenytoin (PHT), 113 valproate (VPA), and 72 phenobarbital (PB)] in 182 individual patients, most of whom were studied on more than one occasion (one visit, 52; two visits, 48; three visits, 33; four visits, 23; five visits, 15; six visits, 4; seven visits, 6; eight visits, 1). Of these patients, 117 had partial seizures that did or did not secondarily generalize, and 65 reported only generalized tonic-clonic seizures. One AED was received by 132 patients, two by 47, and three by 3 patients. These figures include monitored drugs only and omit the benzodiazepines, clobazam, and clonazePam. Methods Age, type of epilepsy, reason for assay, dose of AED(s), and time of last dose and of blood sampling were entered on a specially designed form before the consultation. As study patients arrived at the clinic, a venous blood sample was withdrawn and transferred into a lithium heparin tube for analysis. After the initial interview, the clinician recorded management decisions on the same form. Dose of AED(s), addition or substitution of another AED, advice regarding poor compliance, and time to next appointment were stipulated. The assay result(s) became available -15 min after venipuncture, and the doctor then reviewed decisions while the patient waited. Concentrations of CBZ, PHT, VPA, and PB were measured using an enzyme immunoassay system (EMIT, Syva, Palo Alto, CA, U.S.A.). Only PB

was assayed in the six patients receiving primidone (PRM). Comparisons were made using nonparametric statistical tests, although means are quoted for descriptive purposes. The chi-square test was used for assessing the influence of type of seizure on AED (PHT or CBZ, df = l), concentration category (low, therapeutic, high) on change in AED dose (df = 2), and time-since-dosage on concentration category (df = 12). The AED doses and concentrations for different types of epilepsy were compared by Mann-Whitney U test. Correlations are Spearman rank coefficients. RESULTS

Details of AEDs, doses and concentrations are shown in Table 1. The most commonly prescribed AED was CBZ, used in a larger proportion of patients with partial (70%) than with primary generalised epilepsy (36%, p < 0.001). No other AED was associated with a particular seizure type. Patients with partial seizures received a higher mean dose of CBZ than those experiencing only generalized seizures (860 vs. 600 mg, p < 0.005), although mean concentrations did not differ statistically between the groups (8.6 vs. 7.7 mg/L). Patients experiencing partial seizures received doses of PHT (353 vs. 324 mg) similar to those received by patients with primary generalized epilepsy, but concentrations were higher in the former group (16.7 vs. 13 mg/L, p < 0.01). A wide range of concentrations at each daily dosage schedule was demonstrated for all AEDs. This is shown in Fig. 1 for CBZ. The time elapsed since the last dose correlated highly (p < 0.001) with the classification of results into low, therapeutic, and high values (Fig. 2). This effect was not noted with PHT or VPA. The distribution of assay results for each AED is shown in Fig. 3. Of all concentrations, 35% were categorized as “unexpected” by the examining physician, and in 43% of these (19.2% of all results) a change in decision regarding AED dose was considered appropriate. In 114 (23.3%) of the

TABLE 1. Antiepileptic drug doses and plasma concentrations (mean 5 SD) in 182 actively managed epileptic outpatients

D w Carbamazepine Phenytoin Valproate Phenobarbital Primidone

No. of patients (monotherapy)

Daily dose (mg)

Most common daily dose (mg)

Plasma concentration

106 (69)

743 f 415 336 f 110 1,220 5 785 1 1 1 f 45 509 f 220

800 300 1,000 120 500

8.2 f 3.8 16.2 2 8.2 80.9 ? 42 19.0 f 8.9 17.8 f 9.0”

59 (36) 44 (22) 20 (3) 6 (2)

” Phenobarbital measured. Epilepsia, Vol. 32, No. I , 1991

(mdU

91

ANTIEPILEPTIC DRUG MONITORING CARBAMAZEP" CONCENTRATION

lo.j f

a

r

2.

n

a a a

FIG. 1. Carbamazepine doses and concentrations at the last outpatient attendance in 103 epileptic patients.

a

a a a a

n.103 rs=0.71 a

0

I

I

0.5

1

I 1.5

p