Detection of a drug-drug interaction on population-based phenobarbitone clearance using nonlinear mixed-effects modeling

Objective: Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effects of drug interaction on phenobarbitone clearance values, using 648 serum levels gathered during the routine clinical care of 349 pediatric and adult epileptic patients (age range, 0.4-33.3 years). Patients received phenobarbitone as monotherapy or in combination with either of the antiepileptic drugs carbamazepine or valproic acid. Results: The final model describing phenobarbitone clearance was CL = 52.3·TBW^-0.567. CO, where CL is clearance (ml· kg^-1· h^-1), TBW is total body weight (kg) and CO is a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 46.4(-1/TBW) for those patients receiving concomitant carbamazepine and 0.642 for those patients receiving concomitant valproic acid. Phenobarbitone CL was highest in the very young and decreased in a weightrelated fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered alone or coadministered with carbamazepine or valproic acid. When phenobarbitone was coadministered with carbamazepine or valproic acid, phenobarbitone CL decreased compared with that in monotherapy. Its magnitudes in the presence of carbamazepine are maximal in early childhood (about 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults. Concomitant administration of phenobarbitone and valproic acid resulted in a 35.8% decrease of phenobarbitone CL.