Concurrent HAART and Tuberculosis Treatment: Drug to Drug Interactions

描述（由申请人提供）：本申请是对指导患者导向研究职业发展奖（K23）的请求，以支持Awewura Kwara博士在艾滋病毒和结核病治疗药物代动力学相关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调查人员组成的委员会监督。这个奖项的主要共同导师，dr。David J. Greenblatt和Timothy P. Flanigan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为他的培训和职业发展提供了理想的条件。

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.