1. Intracellular islatravir-triphosphate half-life supports extended dosing intervals.
- Author
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Zang X, Ankrom W, Kraft WK, Vargo R, Stoch SA, Iwamoto M, and Matthews RP
- Subjects
- Humans, Male, Adult, Half-Life, Middle Aged, Young Adult, Deoxyadenosines pharmacokinetics, Deoxyadenosines administration & dosage, Deoxyadenosines therapeutic use, Reverse Transcriptase Inhibitors pharmacokinetics, Reverse Transcriptase Inhibitors therapeutic use, Reverse Transcriptase Inhibitors administration & dosage, Adolescent, HIV-1 drug effects, HIV Infections drug therapy, Aged, Drug Administration Schedule, Polyphosphates, Anti-HIV Agents pharmacokinetics, Anti-HIV Agents therapeutic use, Anti-HIV Agents administration & dosage, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism
- Abstract
Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t
½ ) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½ , supporting further clinical investigation of islatravir administered at an extended dosing interval., Competing Interests: X.Z., W.A., R.V., S.A.S., M.I., and R.P.M. are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or options in Merck & Co., Inc., Rahway, NJ, USA. W.A. was an employee of Merck & Co., Inc., Rahway, NJ, USA, at the time the study was conducted. W.K.K. has no conflicts to report. more...- Published
- 2024
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