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. ? ? ?
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