Abstracts

Rationale: Following oral administration, clobazam is rapidly and quantitatively absorbed into systemic circulation. It is metabolized by the liver via CYP3A4, and, to some extent, by CYP2C19 and CYB2B6, into more than 20 metabolites. The primary route of metabolism is by oxidative demethylation to form N-desmethylclobazam, the active, primary metabolite in systemic circulation. Methods: The pharmacologic activity of N-desmethylclobazam has been demonstrated by several in vitro and in vivo studies. In vitro and ex vivo protein binding studies were conducted via spiked plasma samples and blood samples collected from study participants who were dosed to steady state with clobazam. Plasma concentration data from single-dose trials and multiple-dosage trials in healthy volunteers were used to calculate absorptive and post-absorptive parameters, as well as accumulation factors for N-desmethylclobazam at steady state. Population pharmacokinetic analyses were used to calculate elimination rate constants and clearance values for patient populations. With these results, we pooled pharmacokinetic data from all studies to provide N-desmethylclobazam's pharmacokinetic profile following administration of clobazam. Results: The in vitro plasma protein binding of clobazam and N-desmethylclobazam ranged from 78% to 89% and was concentration-independent. The ex vivo plasma protein binding of both compounds was approximately 90%. In vitro, N-desmethylclobazam was found to be a substrate (but not an inhibitor) of the P-glycoprotein transport system and unlikely to be a substrate for the organic cation or anion transport systems. After an initial dose, clobazam was the predominant moiety (mean AUC_0-inf range of 8,890-11,600 hr*ng/mL and C_max range of 310-402 ng/mL). Following repeated administrations, N-desmethylclobazam becomes the major circulating moiety. Further, steady-state concentrations of N-desmethylclobazam were attained within 2 weeks of dosing. At steady state, the mean AUC and C_max of clobazam were 10,350 hr*ng/mL and 1,076 ng/mL respectively. The corresponding parameters for N-desmethylclobazam were 30,350 hr*ng/mL and 2783 ng/mL, respectively. Conclusions: Based on this population pharmacokinetic analysis, the median half-lives of both clobazam and N-desmethylclobazam were approximately 36 hours and 79 hours, respectively. At steady state, N-desmethylclobazam exposures are approximately 3-5 times greater than clobazam. Renal insufficiency, hepatic dysfunction, or stable dosages of other antiepileptic drugs had no effect on N-desmethylclobazam disposition. Moreover, N-desmethylclobazam had no effect on cardiac conduction, age, weight, race, and sex did not significantly affect N-desmethylclobazam as well.