Genetic-determinants of protease inhibitor pharmacology

描述（由申请人提供）：药物遗传学是一个研究临床药物疗效和毒性变异性的遗传基础的领域。艾滋病药物的一个基本问题是：“什么基因控制着患者体内抗逆转录病毒药物的分布和活性？“本申请中提出的研究是一项概念验证临床研究，旨在解决人类蛋白酶抑制剂分布的遗传决定因素。HIV蛋白酶抑制剂分布的研究具有科学重要性和临床相关性，因为在观察到相同口服剂量后，成人的血浆药物暴露量可能相差10倍。可变的蛋白酶抑制剂浓度与患者的不良结局有关。蛋白酶抑制剂主要通过CYP 3A代谢从体内清除。人与人之间CYP 3A蛋白表达的差异可以解释蛋白酶抑制剂血浆药物暴露的许多变异性。在本申请中，我们将研究蛋白酶抑制剂阿扎那韦的口服清除率依赖于基因决定的CYP 3A 5蛋白表达的假设。了解基因决定的CYP 3A 5表达如何影响阿扎那韦的口服清除率对人类健康至关重要，因为这将填补知识上的重大空白。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加强。这种一刀切的方法忽略了药代动力学变异的根本原因。这种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蛋白酶抑制剂的临床应用。在本申请中，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CYP 3A 5表达，其次确定利托那韦在相同受试者中的作用。这将使我们能够解决利托那韦加强的一刀切方法是否有效地解决了CYP 3A 5蛋白的可变表达。本申请中拟定的研究为前瞻性、对照研究，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一个更好的理解蛋白酶抑制剂药物治疗，并制定一个框架，研究未来的基因型指导的个性化治疗，以改善治疗策略和艾滋病毒/艾滋病患者的结果。

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.