Genetic-determinants of protease inhibitor pharmacology

描述(申请人提供)：药物遗传学是一个研究临床药物疗效和毒性变异的遗传基础的领域。艾滋病毒医学面临的一个基本问题是：“哪些基因控制患者体内抗逆转录病毒药物的处置和活性？”本申请中提出的这项研究是一项概念验证性临床研究，旨在解决人类中蛋白水解酶抑制剂处置的遗传决定因素。HIV-蛋白酶抑制剂处置的研究具有重要的科学意义和临床意义，因为在相同的观察口服剂量后，成人的血浆药物暴露可能会变化10倍。可变的蛋白水解酶抑制物浓度与患者的不良结局有关。蛋白水解酶抑制物主要通过细胞色素P3A代谢从体内清除。不同人之间的CYP3A蛋白表达的差异可能解释了蛋白酶抑制剂血浆药物暴露的大部分差异。在这项应用中，我们将研究一种假设，即蛋白酶抑制剂阿特拉那韦的口服清除依赖于基因决定的CYP3A5蛋白的表达。了解基因决定的细胞色素P3A5的表达如何影响阿扎那韦的口服清除量，这对人类健康很重要，因为这将填补知识的重大空白。目前处理阿扎那韦药代动力学变异性的临床方法是使用利托那韦助推剂。这种一刀切的方法忽略了药代动力学可变性的根本原因。这些知识上的差距阻碍了其他合理策略的发展，以改善阿扎那韦或其他酶抑制剂的临床应用。在这项应用中，我们建议首先确定阿扎那韦的药代动力学是否依赖于基因决定的细胞色素P3A5的表达，然后在相同的受试者中表征利托那韦增强的效果。这将使我们能够解决利托那韦一刀切的方法是否有效地解决了CYP3A5蛋白的可变表达。本申请中提出的研究是前瞻性的、对照的，旨在明确回答特定的药物遗传学问题。我们的长期目标是建立对蛋白酶抑制剂药物治疗的更好理解，并开发一个框架来研究未来以基因为导向的个体化治疗，以改善艾滋病毒/艾滋病患者的治疗策略和结果。

DESCRIPTION (provided by applicant): Pharmacogenetics is a field that investigates the genetic bases for variability in clinical drug efficacy and toxicity. A fundamental unanswered question for HIV medicine is, "What genes control antiretroviral drug disposition and activity in patients?" The study proposed in this application is a proof-of-concept clinical study to address genetic determinants of protease inhibitor disposition in humans. The study of HIV-protease inhibitor disposition is scientifically important and clinically relevant because plasma drug exposures can vary by 10-fold in adults after the same observed oral dose. Variable protease inhibitor concentrations have been linked with poor outcomes in patients. Protease inhibitors are chiefly cleared from the body via CYP3A metabolism. Differences in CYP3A protein expression among persons may explain much of the variability in protease inhibitor plasma drug exposures. In this application we will investigate the hypothesis that the oral clearance of the protease inhibitor, atazanavir, is dependent on genetically-determined expression of the CYP3A5 protein. It is important for human health to understand how genetically-determined expression of CYP3A5 influences the oral clearance of atazanavir, as this would fill a significant gap in knowledge. The current clinical approach to deal with atazanavir's pharmacokinetic variability is to use ritonavir boosting. This one-size-fits- all approach to the problem ignores the underlying cause for pharmacokinetic variability. Such gaps in knowledge hinder the development of other rational strategies to improve the clinical use of atazanavir, or other protease inhibitors. In this application, we propose to first determine whether atazanavir pharmacokinetics are dependent on genetically-determined expression of CYP3A5, and second to characterize the effects of ritonavir boosting in the same subjects. This will allow us to address whether the one-size-fits-all approach of ritonavir boosting effectively addresses variable expression of the CYP3A5 protein. The study proposed in this application is prospective, controlled, and designed to definitively answer specific pharmacogenetic questions. Our long-term goal is to establish a better understanding of protease inhibitor pharmacotherapy and to develop a framework to study future genotype-guided individualized therapies to improve treatment strategies and outcomes in patients with HIV/AIDS.