Display options
Cite
Matthews RP, Ankrom W, Friedman E, et al. Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV. Clin Transl Sci. 2021;14(5):1935-1944doi: 10.1111/cts.13048.
Matthews, R. P., Ankrom, W., Friedman, E., Jackson Rudd, D., Liu, Y., Mogg, R., Panebianco, D., De Lepeleire, I., Petkova, M., Grobler, J. A., Stoch, S. A., & Iwamoto, M. (2021). Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV. Clinical and translational science, 14(5), 1935-1944. https://doi.org/10.1111/cts.13048
Matthews, Randolph P, et al. "Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV." Clinical and translational science vol. 14,5 (2021): 1935-1944. doi: https://doi.org/10.1111/cts.13048
Matthews RP, Ankrom W, Friedman E, Jackson Rudd D, Liu Y, Mogg R, Panebianco D, De Lepeleire I, Petkova M, Grobler JA, Stoch SA, Iwamoto M. Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV. Clin Transl Sci. 2021 Sep;14(5):1935-1944. doi: 10.1111/cts.13048. Epub 2021 Aug 31. PMID: 34463432; PMCID: PMC8504818.
Copy Download .nbib Format: NLM
Share it on

Clin Transl Sci. 2021 Sep;14(5):1935-1944. doi: 10.1111/cts.13048. Epub 2021 Aug 31.

Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.

Clinical and translational science

Randolph P Matthews, Wendy Ankrom, Evan Friedman, Deanne Jackson Rudd, Yang Liu, Robin Mogg, Deborah Panebianco, Inge De Lepeleire, Magdalena Petkova, Jay A Grobler, Selwyn Aubrey Stoch, Marian Iwamoto

Affiliations

  1. Merck & Co., Inc., Kenilworth, New Jersey, USA.
  2. MSD (Europe) Inc., Brussels, Belgium.
  3. SGS Life Science Services, Clinical Pharmacology Unit Antwerpen, Antwerpen, Belgium.

PMID: 34463432 PMCID: PMC8504818 DOI: 10.1111/cts.13048

Abstract

Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high-fat meal. In Study 2, 8 participants per dose received 3 once-weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well-tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half-life was 49-61 h; intracellular islatravir-triphosphate half-life was 118-171 h. Plasma exposure increased in an approximately dose-proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir-triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir-triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

© 2021 Merck Sharp and Dohme Corp. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

References

  1. Antimicrob Agents Chemother. 2012 Sep;56(9):4707-12 - PubMed
  2. Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9274-9 - PubMed
  3. J Biol Chem. 2009 Dec 18;284(51):35681-91 - PubMed
  4. Curr Opin HIV AIDS. 2018 Jul;13(4):294-299 - PubMed
  5. J Infect Dis. 2020 Apr 7;221(9):1398-1406 - PubMed
  6. Antimicrob Agents Chemother. 2013 Dec;57(12):6254-64 - PubMed
  7. Cochrane Database Syst Rev. 2018 Nov 09;11:CD006495 - PubMed
  8. J Biol Chem. 2014 Aug 29;289(35):24533-48 - PubMed
  9. Antivir Ther. 2014;19(2):179-89 - PubMed
  10. Bioanalysis. 2019 Feb 15;: - PubMed
  11. Curr Opin HIV AIDS. 2020 Jan;15(1):27-32 - PubMed
  12. Lancet HIV. 2020 Mar;7(3):e164-e172 - PubMed
  13. Int J Biochem Cell Biol. 2008;40(11):2410-20 - PubMed
  14. Antimicrob Agents Chemother. 2015 Jul;59(7):4190-8 - PubMed
  15. Antimicrob Agents Chemother. 2007 Aug;51(8):2701-8 - PubMed

Publication Types

Grant support