A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A _2A and A _2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.
Competing Interests: Declarations. Ethical approval: The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution (Medical Ethics Committee UZ Ghent). The study was conducted in accordance with the protocol, its amendments, the ethical principles originating from the Declaration of Helsinki, and Good Clinical Practice guidelines. Consent to participate: Written informed consent was provided by all patients before enrollment. Competing interests: PG, MC, YK, KD, LL, KVD, CZM, AS, and EL are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock in Merck & Co., Inc., Rahway, NJ, USA.SR reports grants or contracts during the conduct of the trial for which they received payment; speaker fees to their institution from BMS, MSD, Pfizer, and Roche; travel support for Astellas, MSD, and Sanofi; served on an advisory board for Ipsen, J&J, and MSD; serving as a member of a Data Safety Monitoring Board for all industry-driven phase 1 trials in the department (>20/year); and replacing a member of the CTG (commission for reimbursement of drugs in Belgium) every time a COI is requested per voting.
(© 2024. The Author(s).)