Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that similar to 30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m(2)) and to healthy individuals without renal impairment (matched control group; eGFR >= 90 mL/min/1.73 m(2)). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC(0-infinity)) were similar to 2-fold and similar to 5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC(0-infinity) was similar to 1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function.