Genetic-determinants of protease inhibitor pharmacology

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DESCRIPTION (provided by applicant): Pharmacogenetics is a field that investigates the genetic bases for variability in clinical drug efficacy and toxicity. A fundamental unanswered question for HIV medicine is, "What genes control antiretroviral drug disposition and activity in patients?" The study proposed in this application is a proof-of-concept clinical study to address genetic determinants of protease inhibitor disposition in humans. The study of HIV-protease inhibitor disposition is scientifically important and clinically relevant because plasma drug exposures can vary by 10-fold in adults after the same observed oral dose. Variable protease inhibitor concentrations have been linked with poor outcomes in patients. Protease inhibitors are chiefly cleared from the body via CYP3A metabolism. Differences in CYP3A protein expression among persons may explain much of the variability in protease inhibitor plasma drug exposures. In this application we will investigate the hypothesis that the oral clearance of the protease inhibitor, atazanavir, is dependent on genetically-determined expression of the CYP3A5 protein. It is important for human health to understand how genetically-determined expression of CYP3A5 influences the oral clearance of atazanavir, as this would fill a significant gap in knowledge. The current clinical approach to deal with atazanavir's pharmacokinetic variability is to use ritonavir boosting. This one-size-fits- all approach to the problem ignores the underlying cause for pharmacokinetic variability. Such gaps in knowledge hinder the development of other rational strategies to improve the clinical use of atazanavir, or other protease inhibitors. In this application, we propose to first determine whether atazanavir pharmacokinetics are dependent on genetically-determined expression of CYP3A5, and second to characterize the effects of ritonavir boosting in the same subjects. This will allow us to address whether the one-size-fits-all approach of ritonavir boosting effectively addresses variable expression of the CYP3A5 protein. The study proposed in this application is prospective, controlled, and designed to definitively answer specific pharmacogenetic questions. Our long-term goal is to establish a better understanding of protease inhibitor pharmacotherapy and to develop a framework to study future genotype-guided individualized therapies to improve treatment strategies and outcomes in patients with HIV/AIDS.