title: Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.
abstract: The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.
authors.affiliation: Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yukawa
authors.forename: Masayasu
authors.initials: M
authors.lastname: Satou
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nonaka
authors.forename: Miho
authors.initials: M
authors.lastname: Yukawa
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuroda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012189:Retrospective Studies
chemical_list: D000927:Anticonvulsants; D002998:Clonazepam