TDM & Drug Interactions in HIVinfected Substance Abusers

时分复用

• 批准号: 7069313
• 负责人: Gene D. Morse
• 金额: $ 13.28万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069313
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; capillary electrophoresis; clinical research; drug interactions; high performance liquid chromatography; human subject; liquid chromatography mass spectrometry; pharmacokinetics; plasma; protease inhibitor; protein binding; reverse transcriptase inhibitors; substance abuse related disorder

DESCRIPTION (provided by applicant): This application describes an innovative approach to the rapid assessment of complex drug interactions between protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and commonly prescribed medications including methadone, ethinyl estradiol, fluconazole, pravastatin, and fluoxetine in HIV-infected, substance abusers The proposed methodology employs a Therapeutic Drug Monitoring (TDM) program that will facilitate rapid determination of ART in subjects receiving multiple interacting medications Specific aims 1) Implement a TDM program that will establish a mechanism to investigate protease inhibitor (PI) and NNRTI pharmacokinetics in HIV-infected, substance abusers receiving ART, determine drug exposure parameters (Cmin, AUC) and inhibitory quotients (IQs), 2) Determine the pharmacokinetics of selected interacting medications (methadone, ethinyl estradiol, fluconazole, pravastatin, fluoxetine) in HIV-infected, substance abusers receiving ART, 3) Determine in vitro and ex vivo total and unbound plasma concentrations of protease inhibitors and NNRTIs in HIV-infected, substance abusers utilizing novel analytical approaches including HPLC, LC-MS-MS and capillary electrophoresis, 4) Develop and validate a capillary electrophoresis assay capable of enantiomeric separation to enhance the pharmacokinetic analysis of interacting medications, 5) Examine pharmacogenetic factors that may identify individuals at greater risk for insufficient or excessive systemic drug exposure while receiving complex regimens with multiple drug-drug interactions The proposed TDM-drug-drug interaction program integrates a comprehensive antiretroviral clinical pharmacology research group, an HPLC/LC-MS analytical facility, a pharmacometrics laboratory, a web-based TDM enrollment infrastructure, and four HIV clinical centers caring for substance abusers Innovative pharmacokinetic and pharmacodynamic modeling approaches to assess complex drug-drug interaction analyses of PI and NNRTIs from HIV-infected substance abusers and non-substance abusers will be conducted. Clinical sites will enroll subjects while drug measurement and data analysis will be conducted at the central pharmacology laboratory. These studies will provide insight into clinical interactions that face clinicians and patients today, and identify priority drug interactions that require more traditional pharmacokinetic trials to identify specific mechanisms of interaction.

描述（由申请人提供）：本申请描述了一种快速评估蛋白酶抑制剂和非核苷类逆转录酶抑制剂（NNRTI）之间复杂药物相互作用的创新方法，以及艾滋病毒感染者和药物滥用者常用处方药物（包括美沙酮、乙炔雌二醇、氟康唑、普伐他汀和氟西汀）之间的相互作用。 治疗药物监测 (TDM) 计划将有助于在接受多种相互作用药物的受试者中快速确定 ART 具体目标 1) 实施一项 TDM 计划，建立一种机制来研究 HIV 感染者、接受 ART 的药物滥用者中的蛋白酶抑制剂 (PI) 和 NNRTI 药代动力学，确定药物暴露参数 (Cmin、AUC) 和抑制商 (IQ)，2) 确定接受 ART 的 HIV 感染者、药物滥用者中选定的相互作用药物（美沙酮、乙炔雌二醇、氟康唑、普伐他汀、氟西汀）的药代动力学，3) 利用包括 HPLC 在内的新型分析方法，确定 HIV 感染者、药物滥用者体内蛋白酶抑制剂和 NNRTI 的体外和离体总和未结合血浆浓度， LC-MS-MS 和毛细管电泳，4) 开发和验证能够进行对映体分离的毛细管电泳测定法，以增强相互作用药物的药代动力学分析，5) 检查药物遗传学因素，这些因素可能会识别在接受具有多种药物-药物相互作用的复杂方案时全身药物暴露不足或过量风险较高的个体。 抗逆转录病毒临床药理学研究小组、HPLC/LC-MS 分析设施、药理学实验室、基于网络的 TDM 登记基础设施和四个照顾药物滥用者的 HIV 临床中心 创新的药代动力学和药效学建模方法，用于评估对 HIV 感染的药物滥用者的 PI 和 NNRTI 进行复杂的药物相互作用分析 并将对非药物滥用者进行处理。临床中心将招募受试者，同时药物测量和数据分析将在中心药理学实验室进行。这些研究将深入了解当今临床医生和患者面临的临床相互作用，并确定需要更传统的药代动力学试验来确定特定相互作用机制的优先药物相互作用。