Background:
MK-8527 is an oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two phase 1 trials evaluated ascending single doses (trial A) and ascending multiple doses (trial B) of MK-8527 in adults (aged 18–55 years) without HIV.
Methods:
In trial A, male participants received single oral doses of MK-8527 (0.5–200 mg; fasted) or placebo; 25 mg was also assessed after a high-fat meal. In trial B, male and female participants received 3 once-weekly (QW) oral doses of MK-8527 (up to 40 mg) or placebo. In both trials, participants were randomized (3:1) to receive MK-8527 or placebo. Safety and pharmacokinetics of MK-8527 (plasma) and MK-8527-triphosphate (TP; measured in peripheral blood mononuclear cells [PBMCs]), the active form of MK-8527, were assessed.
Results:
In both trials, MK-8527 was generally well tolerated. In trial A, adverse events (AEs) were reported in 27 of 34 participants (79.4%); 5 (14.7%) were considered drug-related AEs. In trial B, AEs were reported in 29 of 32 participants (90.6%); 11 (34.4%) were considered drug-related AEs. In both trials, all drug-related AEs were mild or moderate, and there were no serious AEs, events of clinical interest, or deaths. After single doses, plasma exposure of MK-8527 increased in an approximately dose-proportional manner, and intracellular exposure of MK-8527-TP (PBMCs) was slightly less than dose proportional over 5–200 mg. Administration of MK-8527 with a meal resulted in a 41% decrease in plasma MK-8527 Cmax, with no effect on plasma MK-8527 AUC0-168, and a 22% increase in intracellular MK-8527-TP Cmax and 58% increase in MK-8527-TP AUC0-168. After multiple QW doses, accumulation of plasma MK-8527 was minimal (range of Cmax and AUC0-168 ratios [Day 15/Day 1] was 0.9–1.4) and accumulation of intracellular MK-8527-TP was moderate (range of Cmax and AUC0-168 ratios was 1.1–1.6; C168 was 1.2–2.4). Across QW doses, the range of MK-8257-TP median Tmax was 10–24 hours, and apparent half-life was 216–291 hours. After administration of MK-8527, the true geometric mean C168 of intracellular MK-8527-TP was above the previously identified pharmacokinetic threshold for antiviral activity against HIV-1 (≥0.2 pmol/106 PBMCs).
Conclusions:
Single (0.5–200 mg) and multiple (QW) doses (up to 40 mg) of MK-8527 administered to adults without HIV were generally well tolerated. The safety and pharmacokinetic profiles of MK-8527 support continued clinical investigation.