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 提交此 K43 申请是为了为我提供环境，以实现成为一名 独立医生/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。为了继续朝着这个目标前进，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 药代动力学药物相互作用和药物基因组学研究基于以下假设： 氟西汀与基于多替拉韦的联合 HIV 抗病毒治疗会增加血浆浓度 多替拉韦和毒性。这种药物相互作用可能会导致药物依从性差、治疗效果不佳 抑郁症和病毒抑制不足。我将在我的研究项目中利用 精心设计的氟西汀和多替拉韦在患有严重艾滋病毒感染者 (PLWH) 中的药代动力学研究 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 感染者之中。我的长期职业研究目标是降低与以下疾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来防治艾滋病毒/艾滋病。 我最初的培训使我在发展临床研究技能方面取得了进步。然而，有 在 K43 颁奖期间我将强调的四个重要领域包括： (1) 设计、实施、监测 临床试验的管理和管理，(2) 群体药代动力学和药效学模型，(3) 药物基因组学，(4) 先进的统计方法。 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 采用基于多替拉韦的抗逆转录病毒疗法进行治疗。 2. 确定多替拉韦和氟西汀在成人抑郁症感染者中的药代动力学。 3. 确定药物基因组学对药代动力学和临床反应的影响，重点关注 代谢酶和转运蛋白的多态性，包括 UGT1A1、SLC22A2、ABCG2、CYP2D6 和 CYP3A4。 。