Concurrent HAART and Tuberculosis Treatment: Drug to Drug Interactions

描述（由申请人提供）：本申请是一项以指导患者为导向的研究职业发展奖（K23）的申请，以支持Awewura Kwara博士在与HIV和TB疗法药代动力学相关的临床研究方面的培训。Kwara博士是布朗医学院的医学助理教授。拟议的培训旨在使他成为一名独立的临床研究者。他的培训将由一个在他所选择的研究领域具有丰富经验的有成就的研究人员委员会监督。该奖项的主要共同导师大卫·J·格林布拉特博士和蒂莫西·P·弗拉尼根博士以及另外五位共同导师将为他提供补充的专业知识和培训。Miriam医院和塔夫茨大学医学院药理学和实验治疗学系的综合资源和设施是他培训和职业发展的理想选择。 结核病是全球艾滋病毒感染的主要和最重要的并发症。在接受结核治疗的患者中，细胞色素P450（CYP）介导的药物-药物相互作用使艾滋病毒感染的并发治疗非常复杂。这些相互作用可能在主要种族之间存在差异，并且无法基于体外模型完全预测。虽然艾滋病毒和结核病的流行对非洲裔人的影响不成比例，但缺乏对这一人群的药物相互作用研究。这是我们的中心假设，种族间或个体间的差异，在活动中的药物代谢酶和这些酶的差异调制的强效酶诱导剂，如利福平，大大有助于差异的反应，同时管理的药物底物。拟定的研究将确定依法韦仑和洛匹那韦/利托那韦在与利福平同时给药之前和期间的药代动力学（PK）参数和耐受性的种族间差异。将研究调节CYP活性以克服这些相互作用的负面影响。此外，将确定利福平和CYP 2B 6 *6携带者状态以及其他宿主因素对依法韦仑处置和应答的相互作用。开发分子和临床模型以识别和预测涉及抗逆转录病毒药物的药物相互作用，将允许对与结核病患者的HIV临床管理相关的现有药物和试验药物进行靶向PK研究。

DESCRIPTION (provided by applicant): This application is a request for a Mentored Patient-Oriented Research Career Developmental Award (K23) to support the training of Dr Awewura Kwara in clinical research related to pharmacokinetics of HIV and TB therapies. Dr Kwara is an Assistant Professor of Medicine at Brown Medical School. The proposed training is designed to enable him to become an independent clinical investigator. His training will be supervised by a committee of accomplished investigators with extensive experience in his chosen area of research. The primary co-mentors for this award, Drs. David J. Greenblatt and Timothy P. Flanigan, together with five additional co-mentors will provide him with complementary expertise and training. The combined resources and facilities at the Miriam Hospital and the Department of Pharmacology and Experimental Therapeutics at Tufts University School of Medicine are ideal for his training and career development. TB is the predominant and most important co-morbidity of HIV infection globally. The concurrent therapy of HIV infection in patients receiving TB treatment is greatly complicated by cytochrome P450 (CYP)-mediated drug-drug interactions. These interactions may vary between the major ethnicities and cannot be entirely predicted based on in-vitro models. While the HIV and TB epidemics have disproportionately affected persons of African descent, drug-drug interaction studies are lacking in this population. It is our central hypothesis that interethnic or interindividual differences in the activities of the CYP drug metabolizing enzymes and differential modulation of these enzymes by potent enzyme inducers such as rifampin contribute substantially to differences in responses to concurrently administered CYP substrates. The proposed research will determine the interethnic differences in the pharmacokinetic (PK) parameters and tolerability of efavirenz and lopinavir/ritonavir before and during concurrent administration with rifampin. Modulation of CYP activity to overcome the negative effect of these interactions will be investigated. Further, the interaction between rifampin and CYP2B6*6 carrier status and other host factors on the disposition and responses to efavirenz will determined. Development of molecular and clinical models to identify and predict drug interactions involving antiretroviral agents will allow for targeted PK studies of current and investigational drugs relevant to the clinical management of HIV in TB patients.