TDM & Drug Interactions in HIVinfected Substance Abusers

描述（由申请人提供）：该应用程序描述了一种创新的方法，用于快速评估蛋白酶抑制剂和非核苷类逆转录酶抑制剂（NNRTIs）之间的复杂药物相互作用，以及hiv感染者常用的处方药，包括美沙酮、炔雌醇、氟康唑、普伐他汀和氟西汀。所提出的方法采用治疗性药物监测（TDM）程序，将有助于快速确定接受多种相互作用药物的受试者的抗逆转录病毒治疗。具体目标1)实施TDM程序，将建立一种机制，调查蛋白酶抑制剂（PI）和NNRTI在hiv感染，接受抗逆转录病毒治疗的药物滥用者中的药代动力学，确定药物暴露参数（Cmin， AUC）和抑制商（iq）。2)确定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）在接受抗逆转录病毒治疗的hiv感染者、药物滥用者中的药代动力学；3)利用HPLC、LC-MS-MS和毛细管电泳等新型分析方法测定hiv感染者、药物滥用者体内和体外蛋白酶抑制剂和nnrti的总浓度和非结合血浆浓度；4)开发并验证一种能够分离对构象的毛细管电泳方法，以加强相互作用药物的药代动力学分析；5)检查药物遗传因素，这些因素可能会识别个体在接受多种药物相互作用的复杂方案时，有更大的全身性药物暴露不足或过量的风险。将采用创新的药代动力学和药效学建模方法来评估HIV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，包括高效液相色谱/LC-MS分析设施、药物计量学实验室、基于网络的TDM登记基础设施和四个治疗药物滥用者的HIV临床中心。临床站点将招募受试者，而药物测量和数据分析将在中心药理学实验室进行。这些研究将为临床医生和患者今天面临的临床相互作用提供见解，并确定需要更多传统药代动力学试验来确定相互作用具体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.