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 estim ate the effects of drug-drug interaction on phenobarbitone clearance v alues, using 645 serum levels gathered during the routine clinical car e of 349 pediatric and adult epileptic patients (age range, 0.4-33.3 y ears). Patients received phenobarbitone as monotherapy or in combinati on with either of the antiepileptic drugs carbamazepine or valproic ac id. Results: The final model describing phenobarbitone clearance was C L = 52.3.TBW-0.567. CO, where CL is clearance (ml.kg(-1).h(-1)), TEW i s total body weight (kg) and CO is a scaling factor for concomitant me dication 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. Phe nobarbitone CL was highest in the very young and decreased in a weight -related fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered a lone or coadministered with carbamazepine or valproic acid. When pheno barbitone was coadministered with carbamazepine or valproic acid, phen obarbitone CL decreased compared with that in monotherapy. Its magnitu des in the presence of carbamazepine are maximal in early childhood (a bout 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults, Concomitant administration o f phenobarbitone and valproic acid resulted in a 35.8% decrease of phe nobarbitone CL.