title: Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.
abstract: A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here.
authors.affiliation: Lundbeck LLC, Deerfield, IL, USA.
authors.forename: Dwain
authors.initials: D
authors.lastname: Tolbert
authors.affiliation: Lundbeck LLC, Deerfield, IL, USA.
authors.forename: Ihor
authors.initials: I
authors.lastname: Bekersky
authors.affiliation: Anoixis Corporation, Natick, MA, USA.
authors.forename: Hui-May
authors.initials: HM
authors.lastname: Chu
authors.affiliation: Anoixis Corporation, Natick, MA, USA.
authors.forename: Ene I
authors.initials: EI
authors.lastname: Ette
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D065697:Cytochrome P-450 CYP2C19 Inducers / Q000494:pharmacology*; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000494:pharmacology*; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D065768:Lennox Gastaut Syndrome / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D065697:Cytochrome P-450 CYP2C19 Inducers; D065689:Cytochrome P-450 CYP2C19 Inhibitors; D065701:Cytochrome P-450 CYP3A Inducers; D001569:Benzodiazepines; D000078306:Clobazam; C024581:N-desmethylclobazam
keywords: Lennox-Gastaut syndrome; clobazam; drug-drug interaction; epilepsy; population pharmacokinetics