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
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DOI：
10.1128/aac.01058-18
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发表时间：
2018-10-01
影响因子：
4.9
通讯作者：
Gindy, Marian E.
中科院分区：
文献类型：
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作者：
Barrett, Stephanie E.;Teller, Ryan S.;Gindy, Marian E.
方案依从性仍然是每日口服药物方案成功治疗和预防人类免疫缺陷病毒（HIV）感染的主要障碍。需要较低频率给药的长效药物制剂提供了改善依从性的机会，并允许在漏服剂量方面有更宽容的选择。在临床环境中施用长效制剂使医疗保健提供者能够直接跟踪依从性。MK-8591（4 =-乙炔基-2-氟-2 =-脱氧腺苷[EFdA]）是一种正在研究的核苷逆转录酶易位抑制剂（NRTTI）候选药物，作为HIV治疗方案的一部分，可能用作暴露前预防（PrEP）的单药。MK-8591的活性三磷酸盐（MK-8591-TP）表现出延长的细胞内持久性，并且与MK-8591的效价一起，支持其考虑延长给药时间。为此，设计了药物洗脱植入器械，以在体外和体内提供延长的MK-8591释放。在啮齿类动物和非人灵长类动物中研究了皮下给药的植入物，以确定MK-8591的药代动力学和MK-8591TP的细胞内水平。根据药代动力学和药效学模型以及MK-8591每周一次口服给药的1a期（Ph1a）和Ph1b期临床研究中生成的数据，对这些数据进行了评价。在动物中单次给药后，MK-8591植入体实现了临床相关的药物暴露和持续药物释放，血浆水平维持超过6个月，相当于有效的MK-8591-TP水平，导致病毒载量降低1.6个对数。MK-8591植入物用于HIV治疗和预防的其他研究是必要的。
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-8591TP. 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.