Pharmacoepidemiologic investigation of a clonazepam-carbamazepine interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.
Nonlinear mixed effects modeling was used to estimate the effects of clonazepam-carbamazepine interaction on clearance values using 359 serum levels gathered from 183 pediatric and adult epileptic patients (age range, 0.3-26.8 years) during their clinical routine care. Patients received the administration of clonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 x TBW(-0.231) x 1.22(CBZ), where CL is total body clearance (mL/kg/h) and TBW is total body weight (kg); CBZ = 1 for concomitant administration of carbamazepine and CBZ = zero otherwise. The final model describing carbamazepine clearance was CL = 92.7 x TBW(-0.394) x DOSE(0-397) x 0.795(CZP), where DOSE is the daily dose of carbamazepine (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance and a 20.5% decrease in carbamazepine clearance.
Yukawa
E
E
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. yukawa@shunsan.phar.kyushu-u.ac.jp
Nonaka
T
T
Yukawa
M
M
Ohdo
S
S
Higuchi
S
S
Kuroda
T
T
Goto
Y
Y
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000097:blood / Q000493:pharmacokinetics*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D010361:Patients / Q000706:statistics & numerical data; D017891:Pharmacoepidemiology; D012189:Retrospective Studies
D000927:Anticonvulsants; D002220:Carbamazepine; D002998:Clonazepam