Background:  IDX899 is a novel NNRTI with potent activity against wild type and NNRTI-resistant HIV-1 in vitro, with a higher genetic barrier to resistance than efavirenz (EFV). Favorable toxicology and clinical micro-dose pharmacokinetics prompted this study to determine dosages for further clinical evaluation.

Methods:  A micro-dose study was conducted with IDX899. Subsequently, single daily doses of 50, 100, 200, 400, 800, and 1200 mg IDX899 were administered sequentially to cohorts of male subjects. Then 2 cohorts received 7 days of dosing with 800 mg once daily or 400 mg twice daily. A female cohort received a single 400-mg dose. Single and multiple dose cohorts each comprised 8 or 10 subjects, respectively, randomized 6:2 or 8:2 (active:placebo). IDX899 was administered orally under fasted (50- to 400-mg doses) then fed (≥200-mg doses) conditions. IDX899 levels were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry method.

Results: Pharmacokinetics were dose-proportional and similar in males and females. IDX899 was well absorbed with an absolute bioavailability of 61%. Food enhanced absorption by ~2x while delaying T_max. Elimination was mostly single phase with t_1/2 ~10 hours. Plasma exposure after repeat dosing, compared to single doses, was similar for 800 once-daily and as much as ~5x higher for 400-mg twice daily. Trough levels were ~2 (range 0.5 to 4.5) and 0.9 (range 0.2 to 2.5) μg/mL for the twice-daily and once-daily regimens, respectively, and exceeded the protein binding-adjusted EC₅₀ (~0.023 μg/mL) by >20- to 40-fold. There were no serious adverse events, dose-limiting toxicities, clustering or dose-dependence of adverse events vital signs, ECG, or laboratory abnormalities. A maximum tolerated dose was not found. For single dose cohorts, 11/49 (22%) IDX899 subjects reported 15 adverse events and 3 of 16 (19%) placebo subjects reported 4 adverse events. For multiple dose cohorts, 7 of 16 (44%) IDX899 subjects reported 14 adverse events, and 1 of 4 (25%) placebo subjects reported 2 adverse events. The drug was well tolerated and the most common adverse event in all groups was headache (n = 5 of 85). Most adverse events were mild. One 800-mg recipient discontinued due to mild rash after the first dose.

Conclusions:  IDX899, dosed at 400 mg twice daily or 800 mg once daily for 7 days, was well tolerated. Trough drug levels exceeded the protein binding-adjusted EC₅₀ by >20- to 40-fold. These results support further clinical studies in patients with HIV-1 infection.