MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development for the treatment of HIV-1 infection. MK-8591-triphosphate (MK-8591-TP), the active phosphorylated anabolite of MK-8591, exhibits a half-life of ~78-128 hours in human peripheral blood mononuclear cell (PBMCs). MK-8591 has been assessed in a monotherapy pharmacodynamic (PD) trial in treatment-naïve HIV-1-infected subjects, where single oral doses of MK-8591 from 0.5 mg – 30 mg demonstrated robust viral load lowering after 7-10 days. Here we present pharmacokinetic (PK) data from a clinical trial examining daily administration of MK-8591 in healthy subjects, and the relationship of these data with data from the antiviral efficacy trial in HIV-1 infected subjects.
In a double-blind, placebo-controlled, three-panel trial, healthy subjects were administered daily placebo or MK-8591 at 5 mg for six weeks, 0.25 mg for four weeks, or 0.75 mg for four weeks (12 active and 4 placebo in each panel). Blood samples were collected for MK-8591 and PBMC MK-8591-TP PK at prespecified times. Vaginal (5 mg, 0.75 mg) or rectal (all three dose levels) biopsies were performed in a subset of subjects to obtain tissue for PK analysis.
All doses were generally well tolerated, with a limited number of mild/moderate adverse experiences reported. Intracellular concentrations of MK-8591-TP that exceeded the EC50 were noted following the first dose of 0.25 mg MK-8591. After 2-3 weeks of dosing, steady-state levels of intracellular MK-8591-TP exceeded 1.0 pmol/million cells on average, comparable to levels seen after dosing 10 mg weekly. In the limited assessment of tissue PK, steady-state levels of active MK-8591-TP at all examined dose levels were comparable to reported levels of tenofovir diphosphate observed in rectal tissue following single doses of emtricitabine/tenofovir.
MK-8591 would be expected to lead to HIV suppression after multiple daily doses as low as 0.25 mg.