Nonclinical and clinical characterization of the absorption, metabolism, and excretion of islatravir.

The development of new and improved antiretroviral therapies that allow for alternative dosing schedules is needed for people living with HIV-1. Islatravir is a deoxyadenosine analog in development for the treatment of HIV-1 that suppresses HIV-1 replication via multiple mechanisms of action, including reverse transcriptase translocation inhibition and delayed chain termination. Islatravir is differentiated from other HIV-1 antiretrovirals by its high potency, long t½, broad tissue distribution, and favorable drug resistance profile. A comprehensive evaluation was performed to provide data on the mass balance, absorption, metabolism, and excretion of islatravir through studies in nonclinical species, and in adults without HIV-1 infection, using radiolabeled islatravir. Islatravir was well absorbed in both nonclinical species and humans following oral administration. The elimination of islatravir occurs primarily by a combination of oxidative deamination to 4'-ethynyl-2-fluoro-2'-deoxyinosine and renal excretion of unchanged islatravir. Islatravir and 4'-ethynyl-2-fluoro-2'-deoxyinosine are the major circulating drug components in all species assessed. Islatravir is readily taken up into cells with efficient phosphorylation to the mono-, di-, and triphosphate forms. The pharmacologically active islatravir triphosphate is the most abundant intracellular phosphorylated species, as shown by the results of ex vivo studies. This characterization of the absorption, metabolism, and elimination of islatravir in humans and nonclinical species supports its further development for the treatment of HIV-1.