Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3

Markowitz, Martin; Gettie, Agegnehu; Bernard, Leslie St.; Andrews, C. Webster; Mohri, Hiroshi; Horowitz, Amir; Grasperge, Brooke; Blanchard, James; Niu, Tao; Sun, Li; Fillgrove, Kerry L.; Hazuda, Daria J.; Grobler, Jay A.

doi:10.1093/infdis/jiz271

Cited by 36 publications

(32 citation statements)

References 29 publications

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“…7b) and demonstrated sustained MK-8591-TP concentrations far in excess of the in vitro 50% effective concentration (EC 50 ) (36). The PCL and EVA implants achieved intracellular MK-8591-TP concentration at the same order of magnitude that conferred complete protection in the rectal SHIV challenge study, 0.8 pmol/10 6 PBMCs (29). From the nonhuman primate study, we predicted the MK-8591 plasma PK in humans from the 50 wt% MK-8591 in PCL implants and compared to clinical PK of once-weekly oral doses of MK-8591.…”

Section: Discussionmentioning

confidence: 92%

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

Barrett

Teller

Forster

et al. 2018

Antimicrob Agents Chemother

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116

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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 and 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.

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Section: Discussionmentioning

confidence: 92%

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

Barrett

Teller

Forster

et al. 2018

Antimicrob Agents Chemother

Self Cite

116

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“…Alternatively, another potent, long-acting small molecule ARV like cabotegravir (46–48) or GS-6297 (49) could be progressed with studies like those shown in this work to achieve the goal of a long-acting subcutaneous implant for the treatment and prevention of HIV infection. 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA, Islatravir, MK-8591) (46–48) is a highly potent nucleoside reverse transcriptase translocation inhibitor: once-weekly oral dosing has demonstrated its ability to protect male rhesus macaques in challenge studies(50). Implantable islatravir implants have demonstrated prophylactic concentrations in a human trial (51, 52).…”

Section: Resultsmentioning

confidence: 99%

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Simpson²,

Sung³

et al. 2019

Preprint

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We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbits and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a dose of 10 µg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. Inflammation in the primates was markedly lower in the placebo group than the active implant. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve sustained target dose we observed unacceptable inflammatory response locally at the implant tissue interface.

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“…Alternatively, another potent, long-acting, small-molecule ARV, like cabotegravir (39-41) or GS-6207 (42), could be progressed with studies like those shown in this work to achieve the goal of a long-acting subcutaneous implant for the treatment and prevention of HIV infection. 4=-Ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) (islatravir; MK-8591) (39-41) is a highly potent nucleoside reverse transcriptase translocation inhibitor: once-weekly oral dosing has demonstrated its ability to protect male rhesus macaques in challenge studies (43). Islatravir implants have demonstrated prophylactic concentrations in a human trial (9,44).…”

Section: Discussionmentioning

confidence: 99%

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Simpson

Sung

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

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Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3

Cited by 36 publications

References 29 publications

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

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

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

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