Background: Atazanavir (ATV) is a potent, safe, and effective once-daily (QD) azapeptide protease inhibitor (PI) currently in Phase III development. Two individual pharmacokinetic (PK) drug interaction studies were conducted. The first study was conducted to assess whether efavirenz (EFV), a metabolic enzyme inducer, had an effect on ATV exposure.

Method: It was an open-label, randomized study, in which 34 healthy subjects received 400 mg ATV QD for 6 days. On Day 7, 34 subjects were randomly assigned to receive either 600 mg ATV QD or co-administered 300 mg ATV QD/100 mg RTV QD, each followed 2 hrs later by 600 mg EFV QD for 14 days. ATV and RTV doses were administered with a light meal. PK profiles were assessed on day 6 for ATV and on day 20 for ATV, RTV and EFV. For Cmax and AUC (TAU) of ATV, point estimates and 95% confidence intervals were constructed for the day 20 to day 6 ratios of geometric means (GM), from the results of analyses of variance (ANOVA) on log (Cmax) and log (AUC [TAU]). Co-administered 600 mg ATV/EFV and 300 mg ATV/100 mg RTV/EFV resulted in a 21% ¯ and 39% ­ in ATV AUC, respectively, vs 400 mg ATV alone. Once-daily co-administration of 300 mg ATV, 100 mg RTV and 600 mg EFV preserved ATV exposure vs 400 mg ATV alone and allows co-administration of ATV and EFV. A second study was conducted to assess whether ATV had an effect on either ethinyl estradiol (EE) (a substrate of UDP-glucuronosyl transferase 1A1) or norethindrone (NE), a combination oral contraceptive (OC). It was an open label, non-randomized study, in which 22 healthy women stabilized on an OC regimen had PK profiles collected after the first 2 weeks of a complete OC cycle (day 1) and after the first 2 weeks of the next OC cycle (day 29) during which 400 mg ATV QD was co-administered from days 16 to 29. To assess the effect of ATV on the PK of either EE or NE, ANOVA were performed on log (AUC) and log (Cmax) of both EE and NE. For each of EE and NE, point estimates and 95% confidence intervals were constructed for the day 29 (ATV + OC) to day 1 (OC alone) ratio of GM for AUC (TAU) and Cmax.

Results: Co-administration of daily doses of OC and 400 mg ATV produced 67% and 110% increases in Cmax and AUC of NE, respectively, and 15% and 48% increases in the Cmax and AUC of EE, respectively, compared to the administration of OC alone.

Conclusions: Co-administration of OC and 400 mg ATV will not impact OC effectiveness. No dose adjustment of OC is recommended. In both studies, no serious laboratory or clinical adverse events were observed.