MK-8591 is a long acting nucleoside reverse transcriptase translocation inhibitor (NRTTI) that has demonstrated potent antiviral activity in HIV-1 infected subjects administered a once-weekly (QW) 10 mg dose as monotherapy in a clinical trial and in SIV-infected rhesus macaque models. MK-8591 extended duration dosing potential was suggested by the long-intracellular half-life of MK-8591-triphosphate (MK-8591-TP) in peripheral blood mononuclear cells (PBMCs) in vitro and in preclinical models. Here we describe the tissue distribution of MK-8591 and its anabolites in rats by quantitative whole body autoradiography and in rhesus vaginal and rectal mucosa by biopsy.
Wistar Hannover rats dosed orally at 50 mpk (mg/kg) of [14C]-MK-8591 were sacrificed at 0.5 hr and 24 hr, cryo-sectioned (40 μm thick sagittal), and phosphor imaged for 4 days. Radioactivity in tissues was quantified using the blood standards along with Raytest AIDA image analysis software. For rectal and vaginal tissue distribution studies, monkeys were dosed 3.9 mpk orally on days 1 and 8. PBMCs were isolated from blood collected at day 1, 7, 14, and 21. Colorectal and vaginal biopsies were collected on days 7 (pre-dose) and 14, pooled separately, and snap-frozen with liquid nitrogen. PBMC and biopsy samples were analyzed by LC-MS/MS.
In rats, MK-8591 distributed widely within 30 min of dosing and was notably enriched in lymphoid tissue (75.9 nmol-eq/g) compared to blood (lymph node:blood ratio = 2.7). MK-8591 remained enriched in lymphoid tissue at 24 hr (11.1 nmol-eq/g; lymph node:blood ratio = 7.1). In rhesus macaques, on days 7 and 14, levels of MK-8591-TP in rectal tissues (36 pmol/g and 31 pmol/g) were similar to those measured in vaginal tissue (49 pmol/g and 78 pmol/g).
The levels of MK-8591-TP achieved in both rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in rectal tissue from human subjects treated with tenofovir disoproxil fumarate. Given the significantly greater potency of MK-8591 (IC50=0.2 nM) compared to TDF (IC50=73 nM), these data suggest utility of MK-8591 for prophylaxis in both men and women. In addition, as lymphoid tissues are sites of active HIV replication and persistence, the observation that MK-8591 is enriched in lymphoid tissues in rats suggests the potential to address the ongoing replication of HIV in lymph nodes.