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：怀孕期间有效的艾滋病毒治疗至关重要，既对生活的妇女的健康 与HIV（WLHIV）和预防围产期HIV传播。但是有知识差距，这限制了我们的 在该特殊人群中部署新有效的抗逆转录病毒疗法的能力。拟议的K23 应用是Ahizechukwu Eke博士对怀孕对新药理学的影响的投资 艾滋病毒药物，包括对依从性测量的影响以及对孕妇这些药物安全的影响。 候选人：Ahizechukwu Eke博士是母亲胎儿医学和临床药理学训练医师科学家 在过去的四年中，他对孕妇药物的临床药理学进行了研究。他 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 通过国际孕产妇青少年艾滋病与药品和科学家的合作 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博士将表征 Tenofovir（TFV）的药代动力学（PK）及其活性形式（细胞内Tenofovir diphosphate - TFV-DP）和 使用PK建模在怀孕中建立PK依从性基准。 AIM 2考试特定于怀孕的安全 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 基于物理的PK（PBPK）建模，以预测母校和胎儿胜利的浓度，Doravirine浓度， 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身体科学家 孕妇的艾滋病毒疗法。他的短期目标和此K23应用的重点是填补空白 他和他的心理团队通过关注这些目标来确定的研究技能：1） 高级PK建模的技能，包括结合依从性和药物计量学的模型； 2）获得技能 通过数据分析和将课程集中在纵向数据分析和专注于纵向数据分析和 药房学研究设计，以及； 3）了解如何开发PBPK模型，可以用来使用 促进孕妇的药物和剂量选择。 EKE博士计划通过与之合作来实现这些目标 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） 和艾滋病毒）；珍妮·谢菲尔德（Jeanne Sheffield）博士（围产期流行病学，孕产妇医学和艾滋病毒）；和Joga Gobburu博士 （药物测量学，PBPK建模）。 环境：约翰·霍普金斯（Hendrix），杜利（Dooley）和谢菲尔德（Sheffield）的机构环境和 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。这些机构与强者之间的长期合作 与ImmaCt成员的合作将为Eke博士提供强烈的心态，以提高他的研究职业。