title: Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.
abstract: Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.
authors.affiliation: Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Minami-ku, Fukuoka, Japan. yukawa@daiichi-cps.ac.jp
authors.forename: E
authors.initials: E
authors.lastname: Yukawa
authors.forename: T
authors.initials: T
authors.lastname: Nonaka
authors.forename: M
authors.initials: M
authors.lastname: Yukawa
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
authors.forename: T
authors.initials: T
authors.lastname: Kuroda
authors.forename: Y
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D017891:Pharmacoepidemiology; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D002998:Clonazepam; D014635:Valproic Acid