Genetic-determinants of protease inhibitor pharmacology

蛋白酶抑制剂药理学的遗传决定因素

• 批准号: 7261841
• 负责人: PETER L. ANDERSON
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261841
• 关键词: AIDS/HIV problem; Address; Adult; African American; Amino Acids; Anti-Retroviral Agents; Atazanavir; CYP3A4 gene; CYP3A5 gene; Clinical; Clinical Research; Controlled Study; Data; Development, Other; Dose; Drug Controls; Drug Exposure; Drug Kinetics; Enzymes; Exposure to; Fill-It; Future; Genes; Genetic; Genetic Determinism; Genotype; Goals; HIV; HIV Infections; HIV Protease Inhibitors; Health; Human; Indinavir; Knowledge; Laboratories; Link; Liver; Medicine; Metabolism; Nelfinavir; Oral; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Pharmacotherapy; Plasma; Protease Inhibitor; Proteins; Race; Research; Retrospective Studies; Ritonavir; Statistically Significant; Toxic effect; Translating; Treatment Failure; United States; Weight; base; clinically relevant; concept; cytochrome P450 3A; design; drug efficacy; experience; improved; prospective; protein expression; response; size

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.

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。 HIV医学的一个基本未解决的问题是：“哪些基因控制患者的抗逆转录病毒药物处置和活性？”该应用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处置的遗传决定因素。 HIV - 抑制剂抑制剂处置的研究在科学上很重要，并且在临床上相关，因为在观察到的口服剂量后，成年人的血浆药物暴露可能会因10倍而变化。可变的蛋白酶抑制剂浓度与患者的预后差有关。蛋白酶抑制剂主要通过CYP3A代谢从体内清除。 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变异性。在此应用中，我们将调查蛋白酶抑制剂Atazanavir的口服清除率取决于CYP3A5蛋白的遗传确定表达。对于人类健康而言，重要的是要了解CYP3A5的遗传确定表达如何影响阿扎纳维尔的口腔清除率，因为这将填补知识的显着空白。当前处理阿扎那维尔（Atazanavir）药代动力学变异性的临床方法是使用ritonavir提升。这一尺寸适合该问题的方法忽略了药代动力学变异性的根本原因。知识中的这种差距阻碍了其他理性策略的发展，以改善阿Zazanavir或其他蛋白酶抑制剂的临床使用。在此应用中，我们建议首先确定Atazanavir药代动力学是否取决于CYP3A5的遗传确定表达，其次是表征同一受试者中利托那韦的效果。这将使我们能够解决利托那韦促进的一大小适合方法是否有效地解决了CYP3A5蛋白的可变表达。该应用中提出的研究是前瞻性，控制和设计的，旨在确切地回答特定的药物遗传学问题。我们的长期目标是更好地了解蛋白酶抑制剂药物疗法，并开发一个框架来研究未来的基因型引导的个性化疗法，以改善艾滋病毒/艾滋病患者的治疗策略和结果。