Pharmacokinetics of aripiprazole and concomitant carbamazepine

The objective of this study was to assess the pharmacokinetics of aripiprazole when coadministered with carbamazepine using an open-label sequential treatment design in patients with schizophrenia or schizoaffective disorder. Nine male patients were enrolled and received aripiprazole monotherapy (30 mg once daily) for 14 days, after which aripiprazole steady-state pharmacokinetics were assessed. Subjects were then administered carbamazepine together with aripiprazole for 4 to 6 weeks. The dose of carbamazepine was titrated to produce a trough serum concentration within the range of 8 to 12 mg/L. Aripiprazole pharmacokinetics were then assessed in the presence of carbamazepine. Six patients completed the study as designed. Coadministration with carbamazepine decreased the values of mean peak plasma concentration and area under the plasma concentration-time curve of aripiprazole by 66% and 71%, respectively (P = 0.001, and 0.002, respectively). Similarly, coadministration with carbamazepine decreased the values of mean peak plasma concentration and area under the plasma concentration-time curve over the 24-hour dosing interval of the major active metabolite of aripiprazole, dehydroaripiprazole, by 68% and 69%, respectively (P < 0.001). Both aripiprazole and dehydroaripiprazole are substrates for the cytochrome P-450 3A4 enzyme which is known to be induced by carbamazepine dosed to steady state. Thus, therapeutic doses of carbamazepine had significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled (to 20-30 mg/d). Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from combination therapy, aripiprazole dose should then be reduced.