Safety and Pharmacokinetics of MK-8527 in Adults Without HIV.

MK-8527 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two Phase 1 trials evaluated single (trial A) and multiple (trial B) ascending doses of MK-8527 in adults without HIV. In trial A, 34 participants were assigned to 1 of 4 panels and randomized to receive single oral doses of MK-8527 (0.5-200 mg) or placebo after fasting, over 3 dosing periods; 25 mg was assessed after a high-fat meal. In trial B, 32 participants were randomized to receive 3 once-weekly (QW) oral doses of MK-8527 (between 5 and 40 mg) or placebo. Safety and pharmacokinetics (PK) of MK-8527 and MK-8527-triphosphate (TP) were assessed. MK-8527 was generally well tolerated with no serious adverse events. Plasma exposure of MK-8527 increased approximately dose-proportionally, and intracellular exposure of MK-8527-TP was slightly less than dose-proportional over administered doses between 5 and 200 mg. Participants who received MK-8527 with a meal showed a 41% decrease in Cmax with no effect on AUC0-168, and a 20%, 22%, and 58% increase in intracellular MK-8527-TP Cmax, C168, and AUC0-168, respectively. Across QW doses, plasma MK-8527 median Tmax ranged from 0.5 to 1 h, and t1/2 was 24-81 h; MK-8527-TP median Tmax ranged from 10 to 24 h on Day 15, and geometric mean apparent t1/2 was 216-291 h. Accumulation of intracellular MK-8527-TP was modest (accumulation ratios Day 15/Day 1 for Cmax and AUC0-168 ranged from 1.1 to 1.6; C168 from 1.2 to 2.4). Single and multiple QW doses of MK-8527 were generally well tolerated in adults without HIV. The safety and PK profiles of MK-8527 support continued clinical development. Trial Registration: EudraCT numbers: 2016-004647-36 (trial A); 2018-000846-20 (trial B).