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Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial.
- Source :
-
The lancet. HIV [Lancet HIV] 2020 Mar; Vol. 7 (3), pp. e164-e172. Date of Electronic Publication: 2020 Jan 03. - Publication Year :
- 2020
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Abstract
- Background: Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection.<br />Methods: This open-label, consecutive-panel, phase 1b trial was done at Charité Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0·5-30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28.<br />Findings: Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78·5-128·0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1·67 log <subscript>10</subscript> copies per mL (95% CI 1·42-1·92) at 10 mg dose to 1·20 log <subscript>10</subscript> copies per mL (0·95-1·46) at 0·5 mg dose. No genetic changes consistent with development of viral resistance were detected.<br />Interpretation: Single doses of islatravir as low as 0·5 mg significantly suppressed HIV-1 RNA by more than 1·0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection.<br />Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adult
Anti-HIV Agents administration & dosage
Anti-HIV Agents adverse effects
Deoxyadenosines administration & dosage
Deoxyadenosines adverse effects
Female
HIV Infections virology
HIV-1 drug effects
HIV-1 enzymology
HIV-1 physiology
Humans
Male
Middle Aged
Reverse Transcriptase Inhibitors administration & dosage
Reverse Transcriptase Inhibitors adverse effects
Young Adult
Anti-HIV Agents pharmacokinetics
Deoxyadenosines pharmacokinetics
HIV Infections drug therapy
Reverse Transcriptase Inhibitors pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3018
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The lancet. HIV
- Publication Type :
- Academic Journal
- Accession number :
- 31911147
- Full Text :
- https://doi.org/10.1016/S2352-3018(19)30372-8