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

氟西汀对尼日利亚患有严重抑郁症的 HIV 感染者中多替拉韦处置动力学的影响

• 批准号: 10538663
• 负责人: WAHEED ADEOLA ADEDEJI
• 金额: $ 6.95万
• 依托单位: COLLEGE OF MEDICINE, UNIVERSITY OF IBADAN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538663
• 关键词: ABCG2 gene; AIDS/HIV problem; Address; Adult; Adverse event; Anti-Retroviral Agents; Antidepressive Agents; Area; Award; CYP2D6 gene; CYP3A4 gene; Caring; Chronic; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Competence; Consensus; Country; Cytochrome P450; Depressed mood; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Environment; Enzymes; Epidemiology; Failure; Fluoxetine; Genes; Genetic Polymorphism; Goals; HIV; HIV Seropositivity; HIV-infected adolescents; Income; Integrase; Internal Medicine; Kinetics; Knowledge; Major Depressive Disorder; Master' s Degree; Mediating; Medical; Medical Residency; Medicine; Membrane Transport Proteins; Mental Depression; Mental disorders; Mentors; Mentorship; Metabolism; Minor; Monitor; Morbidity - disease rate; Nigeria; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physicians; Placebo Control; Plasma; Population; Psychopharmacology; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Safety; Scientist; Selective Serotonin Reuptake Inhibitor; Single Nucleotide Polymorphism; Statistical Methods; System; Testing; Toxic effect; Training; Training Programs; Treatment Failure; Treatment outcome; UGT1A1 gene; Viral; antiretroviral therapy; base; burden of illness; career; comorbidity; design; experience; global health; inhibitor; inhibitor therapy; low and middle-income countries; medication compliance; mortality; neuropsychiatric disorder; neuropsychiatry; pharmacodynamic model; pharmacokinetic model; precision drugs; prevent; professor; programs; response; skills; statistics; systematic review; treatment optimization

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. .

抽象的 正在提交此K43应用程序，为我提供了一个目标，以实现自己的目标 独立医师/科学家研究员和HIV临床药理学研究的领导者和 药物基因组学。为了继续朝着这个目标朝着这个目标的进步，我已经开发了一个全面的K43 指导的研究培训计划，其中包括一个纵向clincal研究项目 药代动力学的药物相互作用和药物基因组研究基于一个假设，即结合 基于Dolutegravir的氟西汀HIV抗病毒治疗将增加血浆浓度 Dolutegravir和毒性。这种药物相互作用可能导致药物依从性不佳，对 抑郁症和病毒抑制不足。我将在我的研究项目中调查这一假设 氟西汀和多洛鲁拉特韦的精心设计的药代动力学研究，患有艾滋病毒（PLWH）的患者 尼日利亚的抑郁症。抑郁症是一种常见的合并症，也是最常见的神经精神疾病 在PLWH中。我的长期职业研究目标是降低与 通过优化低中等收入国家中PLWH的剂量方案的艾滋病毒/艾滋病。 我的最初培训使我能够在发展临床研究技能方面取得了进步。但是，有 我将在K43奖项期间强调的四个重要领域，包括： （1）设计，行为，监视 以及临床试验的管理，（2）种群药代动力学和药效学建模，（3） 药物基因组学和（4）晚期统计方法。 K43研究计划的具体目的是： 1。确定有助于氟西汀在 通过基于Dolutegravir的抗逆转录病毒疗法治疗的抑郁PLWH。 2。确定成人PLWH中Dolutegravir和氟西汀的药代动力学。 3。确定药物基因组学对药代动力学和临床反应的影响 代谢酶和转运蛋白的多态性，包括UGT1A1，SLC22A2，ABCG2，CYP2D6和 CYP3A4。 。