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.

项目总结/摘要 背景：怀孕期间有效的艾滋病毒治疗至关重要，无论是对妇女的健康， 艾滋病毒感染者（WLHIV）和预防围产期艾滋病毒传播。然而，存在知识差距，这限制了我们 在这一特殊人群中部署新的有效抗逆转录病毒治疗药物的能力。建议的K23 应用是由Ahizechukwu Eke博士领导的一项关于怀孕对新的药理学影响的研究。 艾滋病毒药物，包括对坚持措施的影响，以及对孕妇使用这些药物的安全性。 候选人：Ahizechukwu Eke博士是一名接受过孕产妇胎儿医学和临床药理学培训的医生-科学家 世卫组织在过去4年中一直在进行孕妇药物临床药理学研究。他 在约翰霍普金斯大学帮助建立了一个感染艾滋病毒的孕妇队列， 通过国际妇幼青少年艾滋病联合会与药物计量学家和科学家合作， 临床试验（IMPAACT）网络，并撰写了65篇与他的研究相关的PubMed引用的出版物。 研究：在目标1中，在服用替诺福韦艾拉酚胺（TAF）的孕妇中，Eke博士将描述 - 替诺福韦（TFV）及其活性形式（细胞内替诺福韦二磷酸盐- TFV-DP）的药代动力学（PK），和 使用PK建模建立妊娠期PK依从性基准。目的2检查妊娠特异性安全性 TAF通过探索其与妊娠WLHIV代谢综合征发展的相关性，以及Aim 3用途 基于生理学的PK（PBPK）建模以预测母体和胎儿的比替拉韦和多拉韦林浓度， 证实了在一项前瞻性多中心PK队列研究（IMPAACT 2026）中入组妊娠WLHIV的结果。 职业发展计划：Eke博士的长期目标是成为一名独立的医学科学家，专注于 孕妇的艾滋病毒治疗。他的短期目标和K23应用程序的重点是填补以下方面的空白： 他的研究技能，他和他的指导团队已经确定了这些目标的重点：1）成长他的 高级PK建模技能，包括纳入依从性和药物计量学的模型; 2）获得技能 通过数据分析和纵向数据分析的重点课程进行妊娠安全评估， 药物流行病学研究设计; 3）了解PBPK模型是如何开发的，并可用于 方便孕妇选择药物和剂量。Eke博士计划通过与 与其职业目标直接相关的专业知识导师：克雷格亨德里克斯博士和凯利杜利（临床药理学 Jeanne谢菲尔德博士（围产期流行病学、母婴医学和艾滋病毒）和Joga Gobburu博士 （药物计量学，PBPK建模）。 环境：约翰霍普金斯（亨德里克斯，杜利和谢菲尔德）和 马里兰州（Gobburu）大学的药物计量学部是培训和研究的理想场所。 怀孕期间的药物药理学。这些机构与强大的 与IMPAACT成员的合作将为Eke博士提供强有力的指导，以推进他的研究事业。