Islatravir distribution in plasma, peripheral blood mononuclear cells, and mucosal tissues after monthly oral dosing

Objective: – Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under development for HIV-1 treatment. We aimed to evaluate the pharmacokinetics (PK) of islatravir and its active form, islatravir-triphosphate, in blood and mucosal tissues. Design: – This was an exploratory substudy of a randomized, double-blind, placebo-controlled, multicenter, Phase 2a study of once-monthly islatravir in adults at low likelihood of HIV-1 exposure (NCT04003103). Methods: – Participants were randomly assigned 2:2:1 to receive 6 once-monthly oral doses of islatravir 60 mg, islatravir 120 mg, or placebo. Plasma, peripheral blood mononuclear cell (PBMC), and cervical, vaginal, and rectal tissue samples were collected at Weeks 1, 4, 24, and 32. Samples were assayed by liquid chromatography with tandem mass spectrometry. Intercompartmental ratios and regression analyses were assessed. Results: – The analyses included 44 participants who received islatravir 60 mg or 120 mg (73% assigned female at birth; median age 30 years). Following 6 once-monthly doses, islatravir-triphosphate trough concentrations were comparable across homogenized mucosal tissue samples and isolated rectal cells. Median venous whole blood islatravir (total of islatravir and key anabolites) to mucosal tissue islatravir-triphosphate concentration ratios ranged from 0.565 to 1.490 four weeks after the sixth islatravir dose. Adjusted R² coefficients between islatravir concentrations in venous whole blood and islatravir-triphosphate concentrations in rectal, cervical, and vaginal tissues across sampling times were 0.67, 0.76, and 0.75, respectively. Conclusions: – The favorable tissue distribution of islatravir and islatravir-triphosphate following oral administration supports the evaluation of NRTTIs for HIV-1 pre-exposure prophylaxis.