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  • 1
    Online Resource
    Online Resource
    Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention
    American Society for Microbiology ; 2018
    In:  Antimicrobial Agents and Chemotherapy Vol. 62, No. 10 ( 2018-10)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 62, No. 10 ( 2018-10)
    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.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01058-18
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin
    Wiley ; 2021
    In:  The Journal of Clinical Pharmacology Vol. 61, No. 3 ( 2021-03), p. 394-405
    Details
    In: The Journal of Clinical Pharmacology, Wiley, Vol. 61, No. 3 ( 2021-03), p. 394-405
    Abstract: Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV‐1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4‐fold, M9 exposure is increased by only 1.2‐fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4‐fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.
    Type of Medium: Online Resource
    ISSN: 0091-2700 , 1552-4604
    URL: Issue
    URL: Article
    DOI: 10.1002/jcph.v61.3
    DOI: 10.1002/jcph.1747
    RVK:
    XA 52835
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2010253-7
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    In Vitro Evaluation of the Drug Interaction Potential of Doravirine
    American Society for Microbiology ; 2019
    In:  Antimicrobial Agents and Chemotherapy Vol. 63, No. 4 ( 2019-04)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 63, No. 4 ( 2019-04)
    Abstract: Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02492-18
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 4
    Online Resource
    Online Resource
    Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 88, No. 3 ( 2021-11-1), p. 314-321
    Details
    In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 88, No. 3 ( 2021-11-1), p. 314-321
    Abstract: Islatravir (MK-8591) is a novel nucleoside analog in development for the treatment and prevention of HIV-1 infection. Islatravir has potent antiviral activity and a long intracellular half-life. Setting: A 3-panel, randomized, double-blind, placebo-controlled, multiple-dose study in 36 adults without HIV evaluated the safety, tolerability, and pharmacokinetics of islatravir after daily administration. Methods: Islatravir or placebo was administered orally once daily for 42 days (5 mg) or 28 days (0.25 mg; 0.75 mg). Blood samples were taken at prespecified time points for pharmacokinetic analysis of islatravir (plasma) and islatravir-triphosphate (ISL-TP; peripheral blood mononuclear cells [PBMCs]). Rectal and vaginal tissue samples were also collected in a subset of participants. Safety and tolerability were evaluated throughout. Results: The pharmacokinetics of islatravir were approximately dose proportional, with concentrations approaching a steady state between days 14 and 21 in plasma and by day 28 for ISL-TP in PBMCs. Plasma exposure accumulation was 1.5-fold to 1.8-fold, and ISL-TP exposure accumulation was ∼10-fold. The apparent terminal half-life of ISL-TP was 177–209 hours. The ISL-TP pharmacokinetic trough threshold—the minimal concentration required for efficacy—of 0.05 pmol/10 6 cells was achieved after a single administration at all dose levels. Rectal and vaginal tissue also exhibited potentially therapeutic concentrations. Islatravir was generally well tolerated at all doses. Conclusions: ISL-TP levels in PBMCs were above the threshold projected for antiviral efficacy against wild-type HIV after a single 0.25-mg dose. Multiple once-daily dosing of islatravir in adults without HIV was generally well tolerated up to doses of 5 mg administered for up to 6 weeks.
    Type of Medium: Online Resource
    ISSN: 1525-4135
    URL: Article
    DOI: 10.1097/QAI.0000000000002755
    RVK:
    XA 10000
    RVK:
    XA 51942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2038673-4
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  • 5
    Online Resource
    Online Resource
    Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3
    Oxford University Press (OUP) ; 2020
    In:  The Journal of Infectious Diseases Vol. 221, No. 9 ( 2020-04-07), p. 1398-1406
    Details
    In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 221, No. 9 ( 2020-04-07), p. 1398-1406
    Abstract: MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine [EFdA]) is a novel reverse transcriptase–translocation inhibitor. Methods We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3. Results Control macaques were infected after a median of 1 challenge (range, 1–4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P & lt; .0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P = .0003, by the log-rank test). The 0.025-mg/kg dose offered no protection. Conclusions These data support MK-8591’s potential as a preexposure prophylaxis agent.
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
    URL: Article
    DOI: 10.1093/infdis/jiz271
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1473843-0
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