Abstracts

Rationale: Clobazam is an antiepileptic drug (AED) recently approved in the US but with a long tradition of use in patients with epilepsy in Europe. Clobazam shows extensive pharmacokinetic variability. The purpose of this study was to investigate pharmacokinetic variability of clobazam with emphasis on the impact of comedication in patients with epilepsy. Methods: Data from routine TDM-service at the National Center for Epilepsy regarding serum concentration measurements of clobazam and its metabolite desmethylclobazam, 2009-13, were utilized. All included samples were drug-fasting at assumed steady-state. The study was approved by the Regional Ethics Committee. Results: In total, 551 patients were included; 297 w/254 m, average age 27 years (range 1-86). The mean concentration of clobazam was 0.69 µmol/L (range 0.03-2.67) and of N-desmethylclobazam 6.2 µmol/L (range 0.3-57.36). The total C/D-ratio (concentration of clobazam + N-desmethylclobazam/dose) was calculated for patients >18 years of age and for patients < 18 where weight-adjusted doses were available. Mean C/D-ratio was 0.23 (range 0.03-3.29) µmol/L/mg. The pharmacokinetic variability (total C/D-ratio) was 100-fold, where comedication, age, and pharmacogenetic variability may contribute. The impact of inducers on CYP3A4-activity (carbamazepine, phenobarbital) demonstrated a 67% reduction in clobazam C/D-ratio as compared to neutral comedication (p<<0.001), and as suspected, there was no effect of inhibitors (valproate, stiripentol). The impact of the mixed inducers (CYP3A4)/inhibitors (CYP2C19) (phenytoin, oxcarbazepine, felbamate), calculated by the total C/D-ratio, showed a 60% reduction as compared to neutral comedication (1.26 to 0.50 µmol/L/mg, p<<0.001), pointing to a more potent induction of CYP3A4 than inhibition of CYP2C19. In 4.9% (27) patients, where comedication could be excluded as a contributing factor, genetic variability in CYP2C19 (PM) could explain a high desmethylclobazam/clobazam ratio >25, which could be utilized as a screening tool in clinical practice. Conclusions: The present results demonstrate that the pharmacokinetic variability of clobazam is extensive, elucidating a need for individualization of therapy. Comedication is a main contributing factor to the observed variability between patients.