POPULATION-BASED INVESTIGATION OF VALPROIC ACID RELATIVE CLEARANCE USING NONLINEAR MIXED EFFECTS MODELING - INFLUENCE OF DRUG-DRUG INTERACTION AND PATIENT CHARACTERISTICS

Nonlinear mixed effects modeling (NONMEM) was used to estimate the eff ects of drug-drug interaction on valproic acid relative clearance valu es using 792 serum levels gathered from 400 pediatric and adult patien ts with epilepsy (age range, 0.3-54.8 years) during their clinical rou tine care. Patients received valproic acid as monopharmacy or in combi nation with either the antiepileptic drugs, phenobarbital, or carbamaz epine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6 . TBW (kg)(-0.252) . DOSE (mg/kg/day)(0.183) . 0 .898(GEN) . COPB . COCBZ, where COPB equals 1.10 if the patient is tre ated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769 . DOSE (mg/kg/day)(0.179) if the patient is treated with carbama zepine, a value of unity otherwise. Valproic acid relative clearance w as highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern wa s consistent whether valproic acid was administered alone or coadminis tered with phenobarbital or carbamazepine. When valproic acid was coad ministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnit ude in the presence of carbamazepine increased in a valproic acid dail y dose-related fashion. Concomitant administration of phenobarbital an d valproic acid resulted in a 10% increase on valproic acid relative c learance. The clearance in female patients was approximately 10% less than that in male patients.