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 ofclonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 · TBW^-0.231 · 1.22^GBZ, 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 · TBW^-0.394 · DOSE^0.397 · 0.795^GZP 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.