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. .

摘要 这个K43申请正在提交，以提供环境，为我实现我的目标，成为一个 独立的医生/科学家研究者和艾滋病毒临床药理学研究的领导者， 药物基因组学为了继续实现这一目标，我开发了一个全面的K43 指导研究培训计划，包括一个纵向临床研究项目， 基于以下假设的药代动力学药物相互作用和药物基因组学研究： 莫西汀与基于度鲁特韦的联合艾滋病毒抗病毒治疗将增加血浆中 度鲁特韦和毒性。这种药物相互作用可能导致药物依从性差， 抑郁和病毒抑制不足我将在我的研究项目中调查这个假设， 氟西汀和度鲁特韦在HIV感染者（PLWH）中的药代动力学研究 尼日利亚的萧条。抑郁症是一种常见的合并症，也是最常见的神经精神疾病 在艾滋病毒携带者中。我的长期职业研究目标是降低与糖尿病相关的发病率和死亡率。 通过优化中低收入国家艾滋病毒/艾滋病感染者的给药方案。 我最初的培训使我在发展临床研究技能方面取得了进展。但有 我将在K43授予期间强调的四个重要领域包括：（1）设计、实施、监测 临床试验的管理，（2）群体药代动力学和药效学建模，（3） 药物基因组学;（4）先进的统计学方法。 K43研究计划的具体目标是： 1.确定影响氟西汀安全性和有效性的药理学因素， 抑郁的PLWH用dolutegravir为基础的抗逆转录病毒治疗。 2.确定度鲁特韦和百忧解在患有抑郁症的成年PLWH中的药代动力学。 3.确定药物基因组学对药代动力学和临床反应的影响，重点是 代谢酶和转运蛋白（包括UGT 1A 1、SLC 22 A2、ABCG 2、CYP 2D 6和 CYP3A4。 .