Islatravir and lenacapavir fixed-dose combination shows similar bioavailability to single agents in healthy volunteers

Long-acting oral HIV-1 treatments can potentially reduce pill burden, treatment fatigue, suboptimal adherence, and treatment failure. A combination of islatravir, a nucleoside reverse transcriptase translocation inhibitor, and lenacapavir, a capsid inhibitor, is being investigated as a weekly oral HIV-1 treatment. In this open-label, phase 1 study of 93 people without HIV, we investigated pharmacokinetics to evaluate the oral relative bioavailability and safety of a fixed-dose combination (FDC) tablet containing islatravir 2 mg and lenacapavir 300 mg, compared with respective single-agent islatravir 2 mg and lenacapavir 300 mg coadministration under fasted conditions, as well as the food effect for FDC administration. Islatravir pharmacokinetics showed similar mean area under the time-concentration curve extrapolated to infinity (AUC; %GLSM [geometric least-squares mean] ratio [90% confidence interval (CI)]: 107 [97.8-116]) and 36% lower mean peak concentrations (C; %GLSM ratio [90% CI]: 64.4 [56.7-73.1]) for the FDC compared with single-agent coadministration under fasted conditions. Lenacapavir pharmacokinetics showed similar exposures between FDC and single-agent coadministration under fasted conditions (AUC %GLSM ratio [90% CI]:90.2 [72.1-113]; C %GLSM ratio [90% CI]: 103 [80.6-132]). Food had no appreciable effect on islatravir pharmacokinetics, whereas lenacapavir exposure increased, consistent with the known food effect for lenacapavir. Islatravir and lenacapavir were generally well tolerated when coadministered or as an FDC in the fed or fasted state, with a safety profile consistent with known single-agent administration. These results supported and informed phase 3 investigations of an islatravir/lenacapavir FDC tablet as a once-weekly oral treatment option for HIV-1 without regard to food.