Understanding Medication Adherence Benchmarks, Safety and Pharmacometrics of Novel Antiretrovirals in Pregnant Women Living with HIV.

了解感染艾滋病毒孕妇的新型抗逆转录病毒药物的用药依从性基准、安全性和药理学。

• 批准号: 10268254
• 负责人: AHIZECHUKWU C. EKE
• 金额: $ 17.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268254
• 关键词: AIDS prevention; Adherence; Adult; Adverse effects; Anti-Retroviral Agents; Baltimore; Benchmarking; Biometry; Blood; Blood Glucose; Child; Clinical Pharmacology; Clinical Trials Network; Cohort Studies; Collaborations; Cytochrome P450; Data; Data Analyses; Databases; Decision Making; Development; Development Plans; Diphosphates; Dose; Drug Kinetics; Drug Modelings; Drug or chemical Tissue Distribution; Drug usage; Enrollment; Environment; Enzymes; Exposure to; FDA approved; Fetus; Fumarates; Funding; Future; Gestational Diabetes; Goals; HIV; Hair; Health; High Density Lipoproteins; Hospitals; Hypertension; In Vitro; Institution; International Maternal Pediatric Adolescent AIDS Clinical Trials; Investigation; Knowledge; Lead; Logistic Regressions; Maryland; Maternal-fetal medicine; Measures; Mentors; Mentorship; Metabolic; Metabolic syndrome; Modeling; Modification; Mothers; Participant; Perinatal Epidemiology; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacology; Pharmacotherapy; Phase; Physicians; Physiological; Physiology; Plasma; Population; Postpartum Period; Postpartum Women; Pre-Eclampsia; Pregnancy; Pregnancy Trimesters; Pregnant Women; Premature Birth; Prodrugs; Prospective cohort study; PubMed; Publications; Research; Research Design; Research Personnel; Risk; Safety; Scientist; Second Pregnancy Trimester; Serum; Special Population; Spottings; Syndrome; Techniques; Tenofovir; Testing; Therapeutic; Third Pregnancy Trimester; Training; Transferase; Triglycerides; UGT1A1 gene; United States National Institutes of Health; Universities; Uridine Diphosphate; Weight Gain; Woman; Women' s Health; Work; analytical method; anti-viral efficacy; antiretroviral therapy; base; career; career development; cohort; fetal; fetal drug exposure; improved; in silico; in vivo; innovation; medication compliance; medication safety; member; novel; perinatal HIV; pharmacokinetic model; pharmacometrics; physiologically based pharmacokinetics; pregnant; prevent; prospective; safety assessment; secondary analysis; skills; tool; transmission process; viral resistance; waist circumference

PROJECT SUMMARY/ABSTRACT Background: Effective HIV treatment during pregnancy is critically important, both for the health of women living with HIV (WLHIV) and for prevention of perinatal HIV transmission. There are knowledge gaps though, that limit our ability to deploy new effective antiretroviral therapy agents in this special population. The proposed mentored K23 application is an investigation led by Dr. Ahizechukwu Eke on the effects of pregnancy on the pharmacology of new HIV drugs, including effects on adherence measures, and on these drugs’ safety in pregnant women. Candidate: Dr. Ahizechukwu Eke is a Maternal Fetal Medicine and Clinical Pharmacology-trained Physician-Scientist who has spent the past 4 years conducting research on the clinical pharmacology of drugs in pregnant women. He helped establish a cohort of pregnant women living with HIV (WLHIV) at Johns Hopkins, developed strong scientific collaborations with pharmacometricians and scientists through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, and authored 65 PubMed-cited publications related to his research. Research: In Aim 1, among pregnant WLHIV taking tenofovir alafenamide (TAF), Dr Eke will characterize the pharmacokinetics (PK) of tenofovir (TFV) and its active form (intracellular tenofovir diphosphate – TFV-DP), and establish PK adherence benchmarks in pregnancy using PK modeling. Aim 2 examines pregnancy-specific safety of TAF by exploring its association with development of metabolic syndrome in pregnant WLHIV, and Aim 3 uses physiologically based PK (PBPK) modeling to predict maternal and fetal bictegravir and doravirine concentrations, confirming results in pregnant WLHIV enrolling in a prospective multi-center PK cohort study (IMPAACT 2026). Career Development Plan: Dr. Eke’s long term goal is to become an independent physician-scientist focused on HIV therapeutics in pregnant women. His short term goals and the focus of this K23 application, are to fill the gaps in his research skillset that he and his mentoring team have identified by focusing on these objectives:1) To grow his skills in advanced PK modeling, including models that incorporate adherence, and pharmacometrics; 2) to gain skills in safety assessments in pregnancy via data analysis and focused coursework on longitudinal data analysis and pharmaco-epidemiology study design, and; 3) to understand how PBPK models are developed and can be used to facilitate drug and dose selection for pregnant women. Dr Eke plans to achieve these objectives by working with mentors with expertise directly relevant to his career goals: Dr Craig Hendrix and Kelly Dooley (Clinical Pharmacology and HIV); Dr Jeanne Sheffield (Perinatal Epidemiology, Maternal Fetal Medicine, and HIV); and Dr Joga Gobburu (Pharmacometrics, PBPK modeling). Environment: The institutional environments at both Johns Hopkins (Hendrix, Dooley and Sheffield) and the Pharmacometrics Division at the University of Maryland (Gobburu) are ideal for training and research in the pharmacology of drugs in pregnancy. The long-standing collaboration between these institutions and the strong collaboration with members of IMPAACT will provide Dr. Eke with strong mentorship to advance his research career.

项目摘要/摘要 背景：在期间有效的艾滋病毒治疗至关重要，既重要 艾滋病毒（WLHIV）和偏爱围产期HIV转移。 在该特殊人群中部署新有效的抗逆转录病毒疗法的能力。 应用程序是Ahizechukwu Eke博士领导的一项投资，对怀孕的影响对新的新新的新新的新新的新新的新新的新新的新新的新新新的新新新的新新的新新的新新的新新网络的药理学对药理学的影响。 艾滋病毒药物，对依从性措施的影响以及对孕妇的这些药物的安全。 候选人：Ahizechukwu Eke博士是孕产妇胎儿药物和克莱纳学院训练的医师科学家 在过去的四年中，他对孕妇的临床药理学进行了研究 帮助建立了约翰·霍普金斯（Johns Hopkins）患有艾滋病毒（WLHIV）（WLHIV）的孕妇队列 与药剂师和科学家的合作 临床试验（Incract）网络，并撰写了与他的研究相关的65个PubMed引用的出版物。 研究：在AIM 1中，在怀孕的WLHIV服用Tenofovir Alafenamide（TAF）中，Eke博士将描述您 Tenofovir（TFV）的药代动力学（PK）及其活性形式（细胞内替诺福韦双磷酸-TFV-DP） 使用PK建模在怀孕中建立PK依从性。 TAF通过探索其与怀孕WLHIV中代谢综合征的发展的关联，AIM 3用途 基于生理学的PK（PBPK）建模，以预测母体和胎儿Bictigravir和Doravirine概念， 确认在一项前瞻性多中心PK队列研究中招募怀孕的WLHIV（Incract 2026）。 职业发展计划：Eke博士的长期目标是成为专注于的独立医师科学家 孕妇的艾滋病毒治疗疗法。 他和他的指导团队通过将目标集中在这些目标上确定的研究技能：1） 高级PK建模的技能，包含依从性的模型和药物计量学； 通过数据分析通过数据分析和将课程集中于纵向数据分析和 药房学研究设计，3）了解如何使用PBPK模型 促进孕妇的药物和剂量选择，以实现与之合作的目标。 具有与他的职业目标直接相关的专业知识的导师：Craig Hendrix博士和Kelly Dooley（临床药理学） 艾滋病毒）； （药物测量学，PBPK建模）。 环境：Johns Hopkins（Hendrix，Dooley和Sheffield）和The的研究所环境 马里兰州大学（Gobburu）的药物计量学系非常适合培训和研究 妊娠药物的药理学。 与Indract成员与Eke博士合作，提供了强有力的指导，以提高他的研究生涯。