Larson Kajal B, Wang Kun, Delille Cecile, Otofokun Igho, Acosta Edward P
Division of Clinical Pharmacology, University of Alabama at Birmingham, School of Medicine, 1670 University Blvd, Volker Hall, Room 258, Birmingham, AL, 35294-0019, USA.
Clin Pharmacokinet. 2014 Oct;53(10):865-72. doi: 10.1007/s40262-014-0167-9.
Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.
实现最大程度且持久的病毒载量抑制是HIV治疗最重要的目标之一，且与足够的药物暴露直接相关。蛋白酶抑制剂（PIs）是抗逆转录病毒药物中的重要组成部分，在过去一直与口服生物利用度差和服药负担重相关。然而，由于PIs由细胞色素P450（CYP）3A酶代谢，有意抑制这些酶会导致更高的药物暴露、更低的服药负担，从而简化这类药物的给药方案。这就是药代动力学增强的基础。在HIV治疗中，使用两种药代动力学增强剂或增效剂：利托那韦和考比司他。这两种药物都抑制CYP3A4，考比司他是比利托那韦更具特异性的CYP抑制剂。与利托那韦不同，考比司他没有抗逆转录病毒活性。考比司他已在临床试验中得到评估，最近在美国被批准与整合酶抑制剂埃替格韦以及两种核苷（酸）类似物组成固定剂量复方制剂。更多研究正在考察考比司他与各种PIs组成的固定剂量复方制剂。在本综述中，我们总结了关于这些药物以及临床相关药物方案和正在进行的试验的现有知识。还讨论了关于埃替格韦和新型PI TMC319011的研究。
