TDM & Drug Interactions in HIVinfected Substance Abusers

本申请描述了一种快速评估复杂药物相互作用的创新方法 蛋白酶抑制剂和非核苷类逆转录酶抑制剂（NNRTI）之间，通常 处方药物包括美沙酮、炔雌醇、氟康唑、普伐他汀和氟西汀， 建议的方法采用治疗药物监测（TDM） 一项有助于快速确定接受多种相互作用药物治疗的受试者的ART的计划 具体目标1）实施TDM计划，建立研究蛋白酶抑制剂的机制 (PI)和NNRTI在HIV感染者中的药代动力学，接受ART的药物滥用者， 暴露参数（Cmin，AUC）和抑制因子（IQ）， 选定的相互作用药物（美沙酮、炔雌醇、氟康唑、普伐他汀、氟西汀）， 3）测定体外和离体总血浆和未结合血浆 蛋白酶抑制剂和非核苷类逆转录酶抑制剂的浓度在HIV感染，物质滥用者利用新的 分析方法，包括HPLC、LC-MS-MS和毛细管电泳，4）开发和验证 能够分离对映体以增强药代动力学分析的毛细管电泳分析 5）检查可能识别风险更大的个体的药物遗传学因素 在接受多种药物的复杂方案时，全身药物暴露不足或过量- 药物相互作用 拟议的TDM-药物-药物相互作用计划整合了一个全面的抗逆转录病毒临床 药理学研究小组，HPLC/LC-MS分析设施，药物计量学实验室，网络， 基于TDM的注册基础设施和四个艾滋病毒临床中心，为药物滥用者提供护理 评估复杂药物相互作用的药代动力学和药效学建模方法 将对感染艾滋病毒的药物滥用者和非药物滥用者的PI和NNRTI进行分析， 临床研究中心将招募受试者，同时将在 这些研究将提供对临床相互作用的深入了解， 今天的临床医生和患者，并确定优先药物相互作用，需要更传统的 药代动力学试验，以确定具体的相互作用机制。

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.