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: 10709499
• 负责人: AHIZECHUKWU C. EKE
• 金额: $ 17.16万
• 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/10709499
• 关键词: 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; Dryness; Enrollment; Environment; Enzymes; Exposure to; FDA approved; Fetus; Fumarates; Funding; Future; Gestational Diabetes; Glucuronosyltransferase; 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; Physiology; Plasma; Population; Postpartum Period; Postpartum Women; Pre-Eclampsia; Pregnancy; Pregnancy Trimesters; Pregnant Women; Premature Birth; Prevention; 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; 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; 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; 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.

项目概要/摘要 背景：怀孕期间有效的艾滋病毒治疗对于妇女的健康至关重要 感染艾滋病毒 (WLHIV) 并预防围产期艾滋病毒传播。但存在知识差距，这限制了我们 能够在这一特殊人群中部署新的有效抗逆转录病毒治疗药物。拟议的指导型K23 该申请是由 Ahizechukwu Eke 博士领导的一项关于怀孕对新药药理学影响的研究 HIV 药物，包括对依从性措施的影响以及这些药物对孕妇的安全性的影响。 候选人：Ahizechukwu Eke 博士是一位接受过母胎医学和临床药理学培训的医师兼科学家 她在过去 4 年里一直从事孕妇药物的临床药理学研究。他 帮助约翰·霍普金斯大学建立了感染艾滋病毒 (WLHIV) 的孕妇队列，开发了强有力的科学依据 通过国际孕产妇儿科青少年艾滋病与药理学家和科学家合作 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 WLHIV 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)，以及 使用 PK 模型建立妊娠期 PK 依从性基准。目标 2 检查怀孕特定的安全性 TAF 通过探索其与妊娠 WLHIV 中代谢综合征发生的关系，以及 Aim 3 的用途 基于生理学的 PK (PBPK) 模型，用于预测母体和胎儿比克替拉韦和多拉韦林浓度， 确认妊娠 WLHIV 参加前瞻性多中心 PK 队列研究 (IMPAACT 2026) 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师科学家，专注于 孕妇的艾滋病毒治疗。他的短期目标和 K23 申请的重点是填补以下领域的空白： 他和他的指导团队通过关注以下目标确定了他的研究技能：1) 发展他的研究技能 高级 PK 建模技能，包括结合依从性和药理学的模型； 2）获得技能 通过数据分析和纵向数据分析和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模型是如何开发的以及如何用于 方便孕妇选择药物和剂量。 Eke 博士计划通过与 拥有与其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）； Jeanne Sheffield 博士（围产期流行病学、母胎医学和艾滋病毒）；和乔加·戈布鲁博士 （药理学、PBPK 建模）。 环境：约翰霍普金斯大学（亨德里克斯、杜利和谢菲尔德）和 马里兰大学（戈布鲁）的药理学部非常适合进行以下方面的培训和研究： 妊娠期药物的药理学。这些机构与强大的机构之间的长期合作 与 IMPAACT 成员的合作将为 Eke 博士提供强有力的指导，以推进他的研究生涯。

项目成果

The relationship between COVID-19 vaccination status in pregnancy and birthweight.

• DOI: 10.1016/j.ajogmf.2023.101057
• 发表时间: 2023-09
• 期刊: American journal of obstetrics & gynecology MFM
• 影响因子: 6.3

The impact of COVID-19 on the birth rate in Nigeria: a report from population-based registries.

COVID-19 对尼日利亚出生率的影响：来自人口登记处的报告。

• DOI: 10.53388/idr2023004
• 发表时间: 2023
• 期刊: Infectious diseases research
• 作者: Oguejiofor,CharlotteBlanche;Ebubechukwu,KenechiMiracle;Eleje,GeorgeUchenna;Ugwu,EmmanuelOnyebuchi;Enebe,JosephTochukwu;Ekwuazi,KingsleyEmeka;Okoro,ChukwuemekaChukwubuikem;Okpala,BonifaceChukwuneme;Okafor,CharlesChukwunomunso;Eze
• 通讯作者: Eze

Trends and Outcomes of Twin Births in Southwest Nigeria: A 14-Year Retrospective Cohort Study.

尼日利亚西南部双胞胎出生的趋势和结果：14 年回顾性队列研究。

• DOI: 10.14218/erhm.2023.00039
• 发表时间: 2024
• 期刊: Exploratory research and hypothesis in medicine
• 作者: Igbodike,EmekaPhilip;Ijarotimi,OmotadeAdebimpe;Ubom,AkaninyeneEseme;Eleje,GeorgeUchenna;God'swill,ChigboChisom;Okpala,BonifaceChukwuneme;Nwaogu,NwaomaLeslie;Ajenifuja,KayodeOlusegun;Ikechebelu,JosephIfeanyichukwu;Loto,OlabisiM
• 通讯作者: Loto,OlabisiM

Physiologically based pharmacokinetic modeling (PBPK's) prediction potential in clinical pharmacology decision making during pregnancy.

• DOI: 10.1002/ijgo.13150
• 发表时间: 2020-09
• 期刊: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
• 作者: Eke AC;Gebreyohannes RD
• 通讯作者: Gebreyohannes RD

Postpartum Hemorrhage.

• DOI: 10.1056/nejmra1513247
• 发表时间: 2021-04-29
• 期刊: The New England journal of medicine