Evaluation of Potential Drug Interactions Between Armodafinil and Carbamazepine in Healthy Adult Males

Background: Armodafinil has potential use for major depressive episodes associated with bipolar I disorder as adjunctive therapy to maintenance medications. This study evaluated the bidirectional interaction between armodafinil and the mood stabilizer carbamazepine, since both are inducers of, and substrates for, cytochrome P450 (CYP) 3A4. 

Methods: In Group 1 of this open-label, parallel-group study in healthy adult males, subjects received a dose of carbamazepine (200 mg) alone and on day 34 of daily dosing with armodafinil (titrated to 250 mg/day). In Group 2, subjects received a dose of armodafinil (250 mg) alone and on day 32 of twice-daily dosing of carbamazepine (titrated to 400 mg/day). Pharmacokinetic interactions were assessed by changes in mean peak plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0-infinity (AUC0-∞). Adverse events were also assessed.

Results: 80 subjects (40/group) received at least 1 dose of study drug. In Group 1, pretreatment with armodafinil reduced systemic exposure (Cmax and AUC0-∞) to carbamazepine (-12% and -25%, respectively). Likewise, in Group 2, pretreatment with carbamazepine reduced exposure to armodafinil (-11% and 37%, respectively). In each group, exposure to metabolites formed primarily via CYP3A4 increased, as expected. Adverse events observed in each treatment arm were generally consistent with known safety profiles of armodafinil and carbamazepine.

Conclusions: Pretreatment with armodafinil and carbamazepine decreased systemic exposure to one another and increased exposure to their metabolites formed via CYP3A4. Dose adjustment may be required when the compounds are coadministered. Armodafinil and carbamazepine were generally well-tolerated under the conditions studied.