Influence of fluoxetine on the disposition kinetics of dolutegravir among people living with HIV with major depression in Nigeria

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Abstract This K43 appplication is being submitted to provide the environment for me to achieve my goal to become an independent physician/scientist investigator and a leader in the study of HIV clinical pharmacology and pharmacogenomics. To continue my progress towards this goal, I have developed a comprehenisive K43 mentored research training program that includes a a longitudinal clincal research project with nested pharmacokinetic drug interaction and pharmacogenomic studies that are based on a hypothesis that combining fluoxetine with dolutegravir-based combination HIV antiviral treatment will increase the plasma concentration of dolutegravir and toxicity. This drug interaction may result in poor medication adherence, suboptimal treatment of depression and inadequate viral suppression. I will investigate this hypothesis during my research project utilizing well-designed pharmacokinetic studies of fluoxetine and dolutegravir in people living with HIV (PLWH) with major depression in Nigeria. Depression is a common comorbidity and the most common neuropsychiatric disorder among PLWH. My long-term career research goal is to reduce the morbidity and mortality associated with HIV/AIDS through the optimization of dosing regimens in PLWH in low-medium income countries. My initial training has allowed me to make progress in developing clinical research skills. However, there are four important areas that I will emphasize during the K43 award period including; (1) Design, conduct, monitoring and management of a clinical trial, (2) Population pharmacokinetics and pharmacodynamics modeling, (3) Pharmacogenomics, and (4) Advanced statistical methods. The specific aims of the K43 research plan are: 1. To determine the pharmacologic factors that contribute to the safety and effectiveness of fluoxetine among depressed PLWH treated with dolutegravir-based antiretroviral therapy. 2. To determine the pharmacokinetics of dolutegravir and fluoxetine in adult PLWH with depression. 3. To determine the impact of pharmacogenomics on pharmacokinetics and clinical responses focusing on polymorphisms in metabolizing enzymes and transporters including UGT1A1, SLC22A2, ABCG2, CYP2D6 and CYP3A4. .