Background:  Efavirenz (EFV) and carbamazepine (CBZ) are substrates of CYP3A4 or CYP2B6. Both drugs are CYP inducers. The purpose of this study was to assess the multiple-dose pharmacokinetic interaction between EFV and CBZ.

Methods:  An open-label, parallel-arm, 2-period crossover, steady-state pharmacokinetic study was conducted in adult healthy subjects. Arm A (n = 18) received:  EFV 600 mg once daily on days 1 to 14, EFV 600 mg once daily + CBZ on days 15 to 35 (CBZ 200 mg once daily on days 15 to 17, 200 mg twice daily on days 18 to 20, and 400 mg once daily on days 21 to 35. Arm B (n = 18) received:  CBZ 200 mg once daily on days 1 to 3, 200 mg twice daily on days 4 to 6, and 400 mg once daily on days 7 to 21; CBZ 400 mg once daily + EFV 600 mg once daily on days 22 to 35. Pharmacokinetic samples were collected over 24 hours on days 14, 35 (Arm A), and days 21, 35 (Arm B). EFV, CBZ, and CBZ epoxide (CBZE) were analyzed by high performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by non-compartmental analysis. Safety was monitored throughout the study.

Results:  We enrolled 36 subjects (69% male, 67% Caucasian; mean age 30 years, and mean weight 76 kg). There were no serious adverse events. Adverse events and laboratory abnormalities were, in general, typical of those seen with EFV or CBZ administration. Co-administration of EFV + CBZ did not appear to decrease the tolerability of either drug. Pharmacokinetic results are summarized below.

Conclusions:  Co-administration of EFV and CBZ results in a 2-way drug interaction whereby both EFV and CBZ concentrations are decreased. There are no data for this combination using higher doses of either drug; therefore, no dose recommendation can be made. Use of alternate anticonvulsants may be necessary for optimal antiretroviral / anticonvulsant therapy. The drugs were generally safe and well-tolerated when administered alone or in combination.