TDM & Drug Interactions in HIVinfected Substance Abusers

描述(由申请人提供)：本申请描述了一种创新的方法，用于快速评估在HIV感染者和药物滥用者中，蛋白酶抑制剂和非核苷类逆转录酶抑制剂(NNRTI)与常用处方药(包括美沙酮、乙炔雌二醇、氟康唑、普伐他汀和氟西汀)之间的复杂药物相互作用。建议的方法采用治疗药物监测(TDM)计划，该计划将促进在接受多种相互作用药物治疗的受试者中快速测定ART。具体目的1)实施TDM计划，该计划将建立一种机制来研究HIV感染、接受ART药物滥用者的蛋白酶抑制剂(PI)和NNRTI药代动力学，确定药物暴露参数(Cmin，AUC)和抑制商(IQs)，2)测定选择的相互作用药物(美沙酮、乙基雌二醇、氟康唑、普伐他汀、氟西汀)在接受抗逆转录病毒治疗的HIV感染者和药物滥用者中的药代动力学；3)利用包括高效液相、LC-MS-MS和毛细管电泳法在内的新的分析方法，测定HIV感染者和药物滥用者的体外和体外总的和未结合的血浆中蛋白酶抑制剂和NNRTIs的浓度；4)建立和验证能够拆分对映体的毛细管电泳法，以加强相互作用药物的药代动力学分析，5)研究在接受具有多种药物-药物相互作用的复杂方案的同时，可能识别出有更大风险的个体系统性药物暴露不足或过量的药物遗传因素。拟议的TDM-药物-药物相互作用方案将整合一个全面的抗逆转录病毒临床药理学研究小组、一个高效液相/LC-MS分析设施、一个药物计量学实验室、一个基于网络的TDM登记基础设施，以及四个照顾药物滥用者的艾滋病毒临床中心，将进行创新的药代动力学和药效学建模方法，以评估艾滋病毒感染药物滥用者和非药物滥用者的PI和NNRTI的复杂药物-药物相互作用分析。临床站点将招收受试者，而药物测量和数据分析将在中央药理学实验室进行。这些研究将提供对当今临床医生和患者面临的临床相互作用的洞察，并确定需要更传统的药代动力学试验来确定具体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.