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Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01058-18. doi: 10.1128/AAC.01058-18. Print 2018 Oct.

Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention.

Author information

1
Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania, USA Stephanie_barrett@merck.com.
2
Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania, USA.
3
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., West Point, Pennsylvania, USA.
4
Safety Assessment and Laboratory Animals Research, Merck & Co., Inc., West Point, Pennsylvania, USA.
5
Infectious Diseases Discovery Research, Merck & Co., Inc., West Point, Pennsylvania, USA.

Abstract

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (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. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-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 preexposure 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 nonhuman 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 phase 1a (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 a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

KEYWORDS:

HIV prevention; HIV treatment; extended duration; human immunodeficiency virus; long-acting implant

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