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Pharmacoepidemiologic investigation of a clonazepam‐valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients
Author(s) -
Yukawa E.,
aka T.,
Yukawa M.,
Higuchi S.,
Kuroda T.,
Goto Y.
Publication year - 2003
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1046/j.1365-2710.2003.00528.x
Subject(s) - clonazepam , valproic acid , nonmem , concomitant , pharmacokinetics , medicine , pharmacology , drug interaction , anticonvulsant , epilepsy , psychiatry
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.