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MULTIPLE DAILY DOSES OF MK-8591 AS LOW AS 0.25 MG ARE EXPECTED TO SUPPRESS HIV
Randolph P. Matthews1, Deanne J. Rudd1, Vanessa Levine1, Sandra Zhang1, Laura Sterling2, Jay Grobler1, Ryan Vargo1, S. Aubrey Stoch1, Marian Iwamoto1
1Merck & Co, Inc, Kenilworth, NJ, USA,2Celerion, Lincoln, NE, USA
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.