Concurrent HAART and Tuberculosis Treatment: Drug to Drug Interactions

描述(由申请者提供)：本申请是对以患者为导向的研究职业发展奖(K23)的请求，以支持Awewura Kwara博士在与艾滋病毒和结核病治疗的药代动力学相关的临床研究方面的培训。夸拉博士是布朗医学院的医学助理教授。拟议的培训旨在使他能够成为一名独立的临床调查员。他的培训将由一个委员会监督，该委员会由在他选择的研究领域具有丰富经验的有成就的调查人员组成。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，以及另外五名共同导师将为他提供补充专业知识和培训。米里亚姆医院和塔夫茨大学医学院药理学和实验治疗学系的资源和设施结合在一起，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共同发病率。细胞色素P450(CYP)介导的药物-药物相互作用使结核病患者同时治疗HIV感染的过程变得非常复杂。这些相互作用可能在主要种族之间有所不同，不能完全基于体外模型进行预测。虽然艾滋病毒和结核病流行对非洲人后裔的影响不成比例，但在这一人群中缺乏药物-药物相互作用研究。我们的中心假设是，种族间或个体间CYP药物代谢酶活性的差异，以及利福平等有效酶诱导剂对这些酶的不同调节，在很大程度上导致了对同时给予CYP底物的反应的差异。这项拟议的研究将确定在同时服用利福平之前和同时服用利福平之前和期间，依法韦仑和洛皮那韦/利托那韦的药代动力学(PK)参数和耐受性的种族差异。我们将研究如何调节CYP活性以克服这些相互作用的负面影响。此外，利福平和CYP2B6*6载体状态之间的相互作用以及其他宿主因素对Eefavirenz的处置和反应的影响将被确定。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艾滋病毒临床治疗相关的当前和研究药物进行有针对性的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.