TDM & Drug Interactions in HIVinfected Substance Abusers

描述（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逆转录酶抑制剂（NNRTI）与HIV感染者中常用处方药（包括美沙酮、炔雌醇、氟康唑、普伐他汀和氟西汀）之间复杂药物相互作用的创新方法，药物滥用者拟议的方法采用治疗药物监测（TDM）计划，该计划将有助于快速确定接受多种相互作用药物的受试者的ART具体目标1）实施一项TDM计划，该计划将建立一种机制，以研究接受ART的HIV感染者、药物滥用者中蛋白酶抑制剂（PI）和NNRTI的药代动力学，确定药物暴露参数2）确定所选相互作用药物的药代动力学（美沙酮、炔雌醇、氟康唑、普伐他汀、氟西汀），3）利用新的分析方法，包括HPLC，测定HIV感染的物质滥用者中蛋白酶抑制剂和NNRTI的体外和离体总的和未结合的血浆浓度，LC-MS-MS和毛细管电泳，4）开发和验证能够对映体分离的毛细管电泳测定，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，这些因素可以识别在接受具有多种药物相互作用的复杂方案时全身药物暴露不足或过度的风险更大的个体。药物相互作用项目整合了一个全面的抗逆转录病毒临床药理学研究小组，一个HPLC/LC-MS分析设施，一个药物计量学实验室，一个基于网络的TDM注册基础设施，创新的药代动力学和药效学建模方法，以评估来自HIV感染的药物滥用者和非药物滥用者的PI和NNRTI的复杂药物相互作用分析药物滥用者将被拘留。临床研究中心将招募受试者，而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。

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.