Journal Article

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial

Iwamoto, Marian, Zhang, Saijuan, Patel, Munjal, Goodey, Adrian, Reynders, Tom, Haspeslagh, Liesbeth, Rottey, Sylvie, Matthews, Randolph P., Grobler, Jay A., Barrett, Stephanie E., Stoch, S. Aubrey, Vargo, Ryan C.

2021

Overview

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg ( n  = 8, two placebo) and 62 mg ( n  = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 10 6 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 10 6 cells (27.3); 62 mg, 0.272 pmol per 10 6 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy. A subdermal implant of the HIV-1 antiretroviral islatravir delivers sustained drug release over 12 weeks in humans.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/255/1901 / 692/308/153 / 692/699/255/1901 / Adult / Adverse events / Analysis / Anti-HIV Agents - administration & dosage / Anti-HIV Agents - adverse effects / Anti-HIV Agents - pharmacokinetics / Antiretroviral agents / Antiretroviral drugs / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Coefficient of variation / Contraceptives, Vaginal / Deoxyadenosines - administration & dosage / Deoxyadenosines - adverse effects / Deoxyadenosines - pharmacokinetics / Diagnosis / Disease prevention / Double-Blind Method / Hematoma / HIV / HIV (Viruses) / HIV Infections - drug therapy / HIV Infections - genetics / HIV Infections - virology / HIV Reverse Transcriptase - antagonists & inhibitors / HIV-1 - drug effects / HIV-1 - pathogenicity / Human immunodeficiency virus / Humans / Implants / Infectious Diseases / Leukocytes (mononuclear) / Leukocytes, Mononuclear - drug effects / Male / Metabolic Diseases / Middle Aged / Molecular Medicine / Neurosciences / Nucleosides / Peripheral blood mononuclear cells / Pharmacokinetics / Pharmacology / Placebos / Prevention / Prophylaxis / Reverse Transcriptase Inhibitors - administration & dosage / Reverse Transcriptase Inhibitors - adverse effects / Reverse Transcriptase Inhibitors - pharmacokinetics / RNA-directed DNA polymerase / Safety / Sexually transmitted diseases / Testing / Translocation / Transplants & implants / Virus Replication - drug effects