Influence of fluoxetine on the disposition kinetics of dolutegravir among people living with HIV with major depression in Nigeria - In the United States, 1.2 million individuals are HIV positive, of which about one-third have major depressive disorder or notable depressive symptoms. Depression is the most common mental health disorder among people living with HIV (PLWH) and a major barrier to optimal HIV outcomes. Yet, despite widespread use of dolutegravir-based antiretroviral therapy (ART) in the U.S., the safety and pharmacokinetic effects of coadministering second-generation antidepressants remain poorly defined. This study will determine whether fluoxetine, a commonly used second-generation antidepressant, alters dolutegravir exposure or toxicity in PLWH with major depression, with implications for medication adherence, depression control, and HIV viral suppression. Nigeria provides a rigorous, cost-efficient setting for this work because of its high HIV burden, common coinfections, frequent comorbidities, substantial genetic diversity, and complex treatment patterns. Because both drugs are used in U.S. clinical care, the findings will directly inform safer prescribing and improve HIV care for U.S. patients, The long-term goal is to reduce HIV-related morbidity and mortality by optimizing antiretroviral and co- administered medication dosing and improving understanding of drug interactions, variability, and treatment outcomes in diverse patient populations, with findings applicable to patient care in the U.S. By generating actionable evidence for therapies already used in U.S. care, this project will improve clinical decision-making, reduce preventable adverse events, and strengthen the effectiveness of HIV treatment for American patients. This K43 application, through a comprehensive mentored research and career development program, will support my goal of becoming an independent physician-scientist and leader in HIV clinical pharmacology and pharmacogenomics research, My prior training has built a strong foundation in clinical research, and this program will deepen my expertise in clinical trial management, PK/PD modeling, pharmacogenomics, and advanced biostatistical methods. The specific aims are: 1. To determine the pharmacologic factors that contribute to the safety and effectiveness of fluoxetine among depressed PLWH receiving 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.
