Background: Preexposure prophylaxis (PrEP) with antiretroviral drugs has demonstrated efficacy in reducing new HIV infections, although efficacy is tightly linked to good adherence, especially in women. HIV infection continues to be a global epidemic, however, with ~1.8 million new infections reported in 2018. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor with high potency, high barrier to resistance, long t_1/2, and distribution to sites of HIV sexual transmission at levels comparable to those observed in PBMCs. In addition, MK-8591 has demonstrated efficacy with weekly dosing in an SIV challenge prophylaxis study. Thus, MK-8591 appears to have potential as an agent for PrEP.
Methods: Drug-eluting implants were studied in preclinical species to establish general tolerability and pharmacokinetics (PK) of MK-8591 parent and of the active MK-8591-TP (triphosphate). These data, along with data from the SIV challenge study and from previous Phase 1 trials, formed the basis of models for predicting long-term exposures and for establishing a threshold concentration of 0.05 pmol/10⁶ TP in PBMCs. In a double-blind placebo-controlled Phase 1 trial, a single MK-8591 (54mg or 62mg) or placebo implant was placed in subjects for 12 weeks. Safety and tolerability were assessed throughout the trial, and PK was collected for MK-8591 parent and MK-8591-TP until 4 weeks after implant removal. Modeling was conducted to extrapolate and predict MK-8591-TP concentrations.
Results: Implants were generally well tolerated, and PK showed concentrations above target for both implants throughout the study. PK parameter values for MK-8591-TP and the projected duration of the implant above the target are depicted in the table.

[PK parameter values for MK-8591-TP and projected duration of the implant]


Conclusions: MK-8591-eluting implants provide drug release projected to be sufficient for HIV prophylaxis for at least one year. A PrEP implant could provide an attractive option for individuals in whom adherence to a daily PrEP regimen is challenging.