Abstract Details

Title Pharmacokinetics of N-Desmethylclobazam, the Active and Primary Metabolite of Clobazam

Topic Epilepsy

Presentation(s) P01 - (-)

Poster/Presentation
Number 042

Objective

Background Clobazam is rapidly, quantitatively absorbed systemically, and hepatically metabolized by CYP3A4, and, to some extent, by CYP2C19 and CYB2B6, into >20 metabolites. Primary metabolic route is oxidative demethylation (forms N-desmethylclobazam, the active, primary metabolite).

Design/Methods N-desmethylclobazam's pharmacologic activity has been demonstrated by in vitro and in vivo studies. In vitro and ex vivo protein binding studies were conducted via spiked plasma and blood samples collected from participants dosed to steady state with clobazam. Plasma concentration data from single- and multiple-dosage trials in healthy volunteers were used to calculate absorptive and post-absorptive parameters, and N-desmethylclobazam accumulation at steady state. Population pharmacokinetics were used to calculate patients' elimination rate constants and clearance values.

Results In vitro plasma protein binding of clobazam and N-desmethylclobazam ranged from 78%-89% and was concentration-independent. Ex vivo binding of both was [sim]90%. In vitro, N-desmethylclobazam was a substrate (but not an inhibitor) of the P-glycoprotein transport system and was unlikely a substrate for organic cation or anion transport systems. After an initial dose, clobazam was the predominant moiety (mean AUC0-inf range of 8,890-11,600 hr*ng/mL and Cmax range of 310-402 ng/mL). Following repeated administrations, N-desmethylclobazam became the major circulating moiety. N-desmethylclobazam steady-state concentrations were attained ?2 weeks of dosing. Steady state, mean clobazam AUC and Cmax were 10,350 hr*ng/mL and 1,076 ng/mL, respectively. Corresponding parameters for N-desmethylclobazam were 30,350 hr*ng/mL and 2,783 ng/mL.

Conclusions Clobazam's and N-desmethylclobazam's median half-lives were [sim]36 and [sim]79 hours, respectively. Steady state, N-desmethylclobazam exposures were [sim]3-5 times greater than clobazam. Renal insufficiency, hepatic dysfunction, or stable dosages of other AEDs had no effect on N-desmethylclobazam disposition. Age, weight, race, and sex did not significantly affect N-desmethylclobazam parameters, and N-desmethylclobazam had no effect on cardiac conduction.

Authors/Disclosures
Dwain Tolbert, PhD (Lundbeck LLC) PRESENTER	No disclosure on file
	No disclosure on file
Thomas A. Berger, MD (Dept. of Neurology, Medical University of Vienna)	Prof. Berger has received personal compensation in the range of $10,000-$49,999 for serving as a speaker at scientific meetings and participant of local and international advisory boards with various companies producing and markerting treatments for multiple sclerosis (Almirall, Biogen, Biologix, Bionorica, Celgene-BMS, Merck, Novartis, Roche, Sanofi-Genzyme, TG Therapeutics, UCB).

��ɫ��

��ɫ��