Adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of HIV infection. Long-acting drug formulations requiring less frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. Administration of long-acting formulations in a clinical setting enables healthcare providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-deoxyadenosine; EFdA) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for pre-exposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence, and together with the potency of MK-8591, supports its consideration for extended duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo. Implants, administered subcutaneously, were studied in rodents and non-human primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models as well as data generated in Ph1a and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels resulting in 1.6 log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.
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