Pharmacokinetic Drug Interactions Between Clobazam and Drugs Metabolized by Cytochrome P450 Isoenzymes

Study Objective To investigate potential drug‐drug interactions between clobazam and cytochrome P450 ( CYP ) isoenzyme substrates, inhibitors, and inducers. Design Two, prospective, open‐label, single‐center, drug‐drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II – III trials. Setting Clinical research unit. Participants Fifty‐four healthy adult volunteers were enrolled in the two drug‐drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox‐Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. Intervention In the first drug‐drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17–22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP 3A4 or CYP 2C19 inhibition, respectively, on clobazam and its active metabolite N ‐desmethylclobazam ( N ‐ CLB ). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4–19, to study clobazam's effects on CYP 1A2, CYP 2C9, CYP 2D6, and CYP 3A4. Measurements and Main Results In the first DDI study, coadministration of ketoconazole (a CYP 3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity ( AUC 0–∞ ) 54% and decreased clobazam's maximum plasma concentration (C max ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N ‐ CLB to a lesser degree. The CYP 2C19 inhibitor omeprazole increased AUC 0–∞ and C max of N ‐ CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N ‐ CLB has 3–4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug‐drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1‐hydroxymidazolam metabolite, however, decreased by 27% and increased 4‐fold, respectively. Clobazam increased dextromethorphan ( CYP 2D6) AUC 0–∞ by 95% and C max by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP 3A4 or CYP 2C19, or inhibit CYP 2C19, had negligible effects on clobazam or N ‐ CLB . Clobazam did not affect valproic acid or lamotrigine exposures. Conclusion These findings suggest no clinically meaningful drug‐drug interactions between clobazam and drugs metabolized by CYP 3A4, CYP 2C19, CYP 1A2, or CYP 2C9. Concomitant use of drugs metabolized by CYP 2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox‐Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.