Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

doi:10.1046/j.1365-2710.2003.00528.x

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Wiley InterScience

Journal of Clinical Pharmacy and Therapeutics

Volume 28 Issue 6, Pages 497 - 504

Published Online: 3 Dec 2003

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Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

E. Yukawa*, T. Nonaka†, M. Yukawa‡, S. Higuchi§, T. Kuroda† and Y. Goto‡

*Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Minami-ku, Fukuoka, Japan , †Department of Pharmacy, Fukuoka University Hospital, Jonan-Ku, Fukuoka, Japan , ‡Faculty of Pharmaceutical Sciences, Fukuoka University, Jonan-Ku, Fukuoka, Japan and §Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-Ku, Fukuoka, Japan

Correspondence to E. Yukawa, Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan. Tel.: +81 92 541 0161; fax: +81 92 553 5698; e-mail: yukawa@daiichi-cps.ac.jp

KEYWORDS

clearance • clonazepam • drug–drug interaction • NONMEM • valproic acid

Summary

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 1·14^VPA, 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 DOSE^0·159 0·821^CZP 0·896^GEN, 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.

Received 15 March 2003, Accepted 9 September 2003

DIGITAL OBJECT IDENTIFIER (DOI)

10.1046/j.1365-2710.2003.00528.x About DOI