Background:  Efavirenz (EFV) is a substrate of CYP2B6 and 3A4 and an inducer of cytochrome P450 enzymes. Diltiazem (DTZ) and itraconazole (ITR) are substrates and inhibitors of CYP3A4. The purpose of these studies was to assess the multiple-dose pharmacokinetic interaction between EFV and DTZ or ITR.

Methods:  We conducted 2 open-label, parallel-arm, 2-period crossover, multiple-dose pharmacokinetics studies in adult healthy subjects. Study 1 considered EFV-DTZ in 2 arms:  arm A (n = 18) received  EFV 600 mg once daily on days 1 through 14 and EFV 600 mg once daily + DTZ 240 mg once daily on days 15 through 28; arm B (n = 14) received DTZ 240 mg once daily on days 1 through 7 and DTZ 240 mg once daily + EFV 600 mg once daily on days 8 through 21. Study 2 considered EFV-ITR in 2 arms:  arm A (n = 20) received EFV 600 mg once daily on days 1 through 14 and EFV 600 mg once daily + ITR 200 mg twice daily on days 15 through 28; arm B (n = 20) received ITR 200 mg twice daily on days 1 through 14 and ITR 200 mg twice daily + EFV 600 mg once daily on days 15 through 28. Pharmacokinetic samples were collected over 12 or 24 hours and analyzed for EFV, ITR, hydroxyl ITR (HITR), DTZ, desacetyl DTZ (DDTZ), and N-monodesmethyl DTZ (NDTZ) by liquid chromatography/mass spectroscopy/mass spectrometry (LC/MS/MS) or high-performance liquid chromatography/ultraviolet (HPLC/UV). Pharmacokinetics parameters were calculated by non-compartmental analysis. Safety was monitored throughout the study.

Results:  In study 1 (EFV-DTZ), 32 subjects were enrolled (63% male, 72% Caucasian; mean age 32 years and weight 76 kg), of whom 7 subjects did not complete the study. Co-administration of EFV and DTZ resulted in a significant decrease in the exposure of DTZ and its 2 major metabolites. Increase in EFV exposure was modest, which does not appear to be clinically relevant. In study 2 (EFV-ITR), 40 subjects were enrolled (68% male, 73% Caucasian; mean age 31 years and weight 76 kg), of whom 6 subjects did not complete the study. Co-administration of EFV and ITR resulted in a 1-way drug interaction whereby ITR and HITR concentrations were decreased. There was no effect on EFV exposure. The drugs were generally safe and well tolerated when administered alone or in combination.

Conclusions:  The concomitant administration of EFV with DTZ or ITR did not adversely affect the safety profile of EFV, DTZ, or ITR. No dosage adjustment is necessary for EFV when co-administered with DTZ or ITR; DTZ dose adjustment should be guided by clinical response. There are no data using higher doses of ITR; therefore, no dose recommendation can be made. Use of alternate treatment may be necessary for optimal antifungal therapy.