Background:  Twice-daily atazanavir (ATV) increases ATV exposures without the need for ritonavir (RTV). ATV 300 mg twice-daily given with raltegravir (RAL) 400 mg twice daily is being explored as RTV and nucleoside-sparing treatment strategy. The 2-way pharmacokinetic interaction and safety of twice-daily ATV (300 mg) and RAL (400 mg) was assessed.

Methods:  We treated 22 healthy subjects, of whom 19 completed. Subjects received RAL 400 mg twice daily days 1 to 5, ATV 300 mg twice daily days 6 to 12, and ATV 300 + RAL 400 mg twice daily days 13 to 26, all with a light meal. Serial blood samples were collected for 12 hours post-morning dose on days 5, 12, and 26. Pharmacokinetic parameters were derived using non-compartmental methods. General linear models were used for exposure comparisons. Safety assessment, clinical labs, and serial ECG (pre-dose, and 2 and 6 hours) were obtained.

Results:  When co-administered with RAL, the geometric mean C_max, AUC, and C_min for ATV twice daily were reduced by 11% (90%CI 6 to 17%), 17% (11 to 22%), and 29% (22 to 35%) compared to ATV twice daily alone. ATV geometric mean C_min was 817 ng/mL (range 250 to 1550 ng/mL); C_min was moderately lower compared to ATV/RTV (historical). ATV twice daily increased RAL geometric mean C_max, AUC, and C_min by 39% (–1 to 96%), 54% (14 to 108%), and 48% (8 to 102%). No ECG changes were noted with RAL alone. No mean QTcF prolongation was noted during study. Mean QRS increase from baseline (mean 88 ms, range 72 to 101 ms) 2 hours post dose was 11.0 ms (range 2 to 25 ms) on day 12; no QRS interval was >120 ms with ATV twice daily ± RAL. Mean PR change from baseline (mean 153 ms, range 122 to 183 ms) 2 hours post dose on day 12 was 37 ms (range 17 to 63 ms). Compared to historical data for ATV/RTV, hyperbilirubinemia is comparable, PR increase comparable/slightly higher, and QRS widening greater with ATV twice daily ± RAL. Gastrointestinal-type adverse events were unremarkable. The incidence of adverse events was similar when ATV twice-daily was administered alone or with RAL.

Conclusions:  Upon co-administration of ATV 300 mg twice daily with RAL 400 mg twice daily, ATV AUC and C_min were decreased relative to ATV twice daily alone; all ATV C_min were >10´ wild-type HIV EC₉₀ (EC₉₀ is 14 ng/mL). ATV twice daily increased RAL to a similar extent as previously with once-daily ATV ± RTV. The clinical relevance of QRS widening with ATV twice daily is unclear and warrants further investigation. In this study, ATV twice daily and RAL twice daily alone and co-administered appeared safe and well-tolerated.