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

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.
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Grant Number: 5K43TW011995-04
NIH Institute/Center: NIH
Principal Investigator: WAHEED ADEDEJI