Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 88; no. 3; p. 314
• Main Authors: Matthews, Randolph P, Jackson Rudd, Deanne, Zhang, Saijuan, Fillgrove, Kerry L, Sterling, Laura M, Grobler, Jay A, Vargo, Ryan C, Stoch, S Aubrey, Iwamoto, Marian
• Format: Journal Article
• Language: English
• Published: United States 01.11.2021
• Subjects: Administration, Oral; Antiviral Agents - therapeutic use; Deoxyadenosines - pharmacokinetics; Deoxyadenosines - therapeutic use; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Half-Life; HIV Seronegativity; Humans; Leukocytes, Mononuclear
• ISSN: 1944-7884
• DOI: 10.1097/QAI.0000000000002755

Islatravir (MK-8591) is a novel nucleoside analog in development for the treatment and prevention of HIV-1 infection. Islatravir has potent antiviral activity and a long intracellular half-life. A 3-panel, randomized, double-blind, placebo-controlled, multiple-dose study in 36 adults without HIV evaluated the safety, tolerability, and pharmacokinetics of islatravir after daily administration. Islatravir or placebo was administered orally once daily for 42 days (5 mg) or 28 days (0.25 mg; 0.75 mg). Blood samples were taken at prespecified time points for pharmacokinetic analysis of islatravir (plasma) and islatravir-triphosphate (ISL-TP; peripheral blood mononuclear cells [PBMCs]). Rectal and vaginal tissue samples were also collected in a subset of participants. Safety and tolerability were evaluated throughout. The pharmacokinetics of islatravir were approximately dose proportional, with concentrations approaching a steady state between days 14 and 21 in plasma and by day 28 for ISL-TP in PBMCs. Plasma exposure accumulation was 1.5-fold to 1.8-fold, and ISL-TP exposure accumulation was ∼10-fold. The apparent terminal half-life of ISL-TP was 177-209 hours. The ISL-TP pharmacokinetic trough threshold-the minimal concentration required for efficacy-of 0.05 pmol/106 cells was achieved after a single administration at all dose levels. Rectal and vaginal tissue also exhibited potentially therapeutic concentrations. Islatravir was generally well tolerated at all doses. ISL-TP levels in PBMCs were above the threshold projected for antiviral efficacy against wild-type HIV after a single 0.25-mg dose. Multiple once-daily dosing of islatravir in adults without HIV was generally well tolerated up to doses of 5 mg administered for up to 6 weeks.