The potential to enhance adherence with less frequent dosing would represent a major advance for the treatment and prevention of HIV. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with sub-nM potency that is in early stage clinical development. The phosphorylated anabolites of MK-8591, including the active triphosphate (MK-8591-TP), exhibit protracted intracellular persistence in human PBMCs and macrophages, protecting cells from infection in the absence of continued exposure in vitro. The potency, pharmacokinetic, and physical properties of MK-8591 are ideal for extended duration dosing.
MK-8591 efficacy was evaluated in a SIVmac251-infected rhesus macaques dosed once weekly (QW) with 1.3 to 18.2 mg/kg. Doses were chosen on the basis of rhesus PK and intracellular NTP levels designed to match levels associated with antiviral efficacy in PBMCs. Plasma viral loads and MK-8591 concentrations (measured pre-dose through day 42) were used to a develop a PK/PD model and select ph1 doses for evaluation as QW oral dose in healthy subjects and enable dose selection for the development of long-acting parenteral formulations.
Baseline SIV viral loads in monkeys ranged from 106 to 108 copies per ml. After administration of QW doses of 3.9 to 18.2 mg/kg MK-8591, monkeys with viral loads < 108 exhibited near maximal 2-log drops in viral loads and maintained suppression of viremia for at least 7days. MK-8591-TP concentrations of ≥0.53 pmol/106 PBMCs were associated with QW efficacy.
In healthy volunteers, single doses of 10 mg and greater were able to achieve these levels of MK-8591-TP for at least 7 days, suggesting the potential for QW antiviral efficacy at a low dose.
Finally, long-acting parenteral formulations of MK-8591 exhibited continuous, extended-duration drug release in rodents with MK-8591 plasma levels comparable to those achieved in rhesus and humans and duration of release exceeding 6 months.
The antiviral efficacy in an SIV rhesus macaque model when dosed QW together with the human PK data, suggest the potential for MK-8591 QW oral dosing in the clinic and a low dose compatible with delivery via long-acting formulations. MK-8591 QW oral and long-acting parenteral formulations with potential for six months or longer duration would represent a potential paradigm shift as a single agent for prevention of HIV infection or as a component of an extended dosing regimen for HIV treatment.