Population Pharmacokinetic Modeling and Clinical Trial Simulation to optimize HIV Prevention in Pregnancy and Postpartum

群体药代动力学模型和临床试验模拟可优化妊娠期和产后的艾滋病毒预防

• 批准号: 10316144
• 负责人: Craig Walter Hendrix
• 金额: $ 23.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316144
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Adherence; Behavioral; Biological; Blood; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Communicable Diseases; Data; Data Set; Dose; Drug Kinetics; Enrollment; Evaluation; Excretory function; FDA approved; Fetus; Fumarates; Future; Glomerular Filtration Rate; Goals; HIV; Incidence; International Maternal Pediatric Adolescent AIDS Clinical Trials; Kidney; Liquid substance; Modeling; National Institute of Child Health and Human Development; Oral; Performance; Perinatal transmission; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physiological; Plasma; Population; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prevention; Protective Agents; Randomized Clinical Trials; Renal clearance function; Reporting; Research; Research Priority; Risk; Risk Factors; Safety; Sampling; Second Pregnancy Trimester; Secondary to; Tenofovir; Third Pregnancy Trimester; Tissues; Variant; Woman; adverse pregnancy outcome; appropriate dose; cervicovaginal; cis-female; cohort; comparative; design; efficacy study; emtricitabine; experience; falls; infant outcome; men who have sex with men; novel; pharmacokinetic model; pharmacometrics; pre-exposure prophylaxis; pregnant; prospective; rectal; response; simulation; sound; transgender women; AIDS prevention; Acquired Immunodeficiency Syndrome; Adherence; Behavioral; Biological; Blood; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Communicable Diseases; Data; Data Set; Dose; Drug Kinetics; Enrollment; Evaluation; Excretory function; FDA approved; Fetus; Fumarates; Future; Glomerular Filtration Rate; Goals; HIV; Incidence; International Maternal Pediatric Adolescent AIDS Clinical Trials; Kidney; Liquid substance; Modeling; National Institute of Child Health and Human Development; Oral; Performance; Perinatal transmission; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physiological; Plasma; Population; Postpartum Period; Postpartum Women; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prevention; Protective Agents; Randomized Clinical Trials; Renal clearance function; Reporting; Research; Research Priority; Risk; Risk Factors; Safety; Sampling; Second Pregnancy Trimester; Secondary to; Tenofovir; Third Pregnancy Trimester; Tissues; Variant; Woman; adverse pregnancy outcome; appropriate dose; cervicovaginal; cis-female; cohort; comparative; design; efficacy study; emtricitabine; experience; falls; infant outcome; men who have sex with men; novel; pharmacokinetic model; pharmacometrics; pre-exposure prophylaxis; pregnant; prospective; rectal; response; simulation; sound; transgender women

ABSTRACT Pre-exposure prophylaxis (PrEP) with oral tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (F or FTC) (F/TDF) is recommended during pregnancy for women at risk for HIV acquisition. F/tenofovir alafenamide fumarate (F/TAF) is not yet approved for PrEP in cisgender women due to lack of efficacy data. Despite the importance of HIV prevention in pregnancy, pregnant women have been excluded from PrEP efficacy studies. PrEP efficacy in pregnancy cannot be extrapolated from non-pregnant populations, as multiple studies indicate that TFV concentrations fall substantially in the 2nd and 3rd trimesters due to increased renal clearance and volume of distribution. Significant declines in FTC concentration are also reported largely due to increased renal excretion. Unlike TDF, TAF has minimal renal clearance, though other changes associated with pregnancy may also reduce its concentration. Given the high TFV blood concentrations required in non-pregnant women to achieve protective concentrations in cervicovaginal tissue, near perfect adherence to F/TDF is required to achieve HIV protection. The decreased TFV and FTC concentrations observed during pregnancy raise concern that a significant proportion of pregnant women on F/TDF for PrEP would not achieve protective concentrations without upward dose adjustment. In anticipation of the eventual approval of F/TAF for HIV prevention in cisgender women, evaluation of pharmacokinetic (PK) parameters and appropriate dosing of both F/TDF and F/TAF for PrEP in pregnancy is critically important to the prevention of both maternal and perinatal transmission. To assist with the future design of clinical trials to correct for this probable underdosing of F/TDF and, possibly, F/TAF, we propose an exploration of F/TAF and F/TDF PK parameters in pregnancy and postpartum. We plan to use F/TDF and F/TAF PK data from completed clinical studies enrolling non-pregnant and pregnant cisgender women in both the treatment and prevention settings, including IMPAACT 1026s, CONRAD 137 and 140, MTN 001, HPTN 066, Partners PrEP, Partners Demonstration Project, and several Gilead PK trials. Our specific aims are to: 1. Build a population PK model of F/TDF and F/TAF related drug analytes with special focus on timing relative to pregnancy in addition to variation in demographic and physiologic variables and building on existing PK models and 2. Simulate two clinical trials, one of F/TAF and one of F/TDF PrEP dosing in pregnancy and postpartum to assist with the future design of clinical trials to validate pregnancy- adjusted doses to maintain non-pregnant levels of HIV protection throughout pregnancy. This population PK research is the critical next step toward a prospective randomized clinical trial to better protect pregnant women and their fetuses against HIV acquisition and is in line with the NICHD Maternal and Pediatric Infectious Disease Branch and Office of AIDS research's stated high priority of “reducing the incidence of HIV” and “adverse pregnancy and infant outcomes related to prevention”.

抽象的 用口服Tenofovir（TFV）毒死式（TDF）和Emtricitabine（F或 FTC）（F/TDF）建议在怀孕期间，患有艾滋病毒感染风险的妇女。 f/tenofovir alafenamide 由于缺乏效率数据，富马酸盐（F/TAF）尚未批准在Cisgender妇女中的PREP。尽管有 预防艾滋病毒在怀孕中的重要性，孕妇被排除在预科效率研究之外。 妊娠的准备效率不能从非怀孕人群中推断出来，因为多个研究表明 由于肾脏清除率增加，TFV浓度在第二和第三个三重体中大大落在 分布量。 FTC浓度的显着下降也很大程度上据报道 肾脏排泄。与TDF不同，TAF具有最小的肾脏清除率，尽管其他变化与 怀孕也可能降低其浓度。 考虑到非孕妇需要高的TFV血液浓度才能达到保护浓度 在宫颈阴道组织中，需要几乎完全遵守F/TDF才能获得HIV保护。拒绝了 在怀孕期间观察到的TFV和FTC浓度引起了人们的关注，很大一部分 f/tdf进行准备的孕妇将无法获得保护浓度而没有上剂量 调整。预计F/TAF最终批准了cisgender妇女预防艾滋病毒的艾滋病毒， 药代动力学（PK）参数的评估以及F/TDF和F/TAF的适当给药以进行准备 怀孕对于预防母体和围产期传播至关重要。协助 临床试验的未来设计，以纠正这种有问题的f/tdf剂量的剂量，并且可能是f/taf，我们 提议在怀孕和产后对F/TAF和F/TDF PK参数的探索。我们计划使用 来自已完成的临床研究的F/TDF和F/TAF PK数据招募了非怀孕和怀孕的cisgender 妇女在治疗和预防环境中，包括Incract 1026，Conrad 137和140，MTN 001，HPTN 066，Partners Prep，Partners示范项目和几项Gilead PK试验。 我们的具体目的是：1。与f/tdf和f/taf相关的药物分析物的人群PK模型 除了人口统计学和生理变量的变化外，还要特别关注与怀孕的时间安排 并建立在现有的PK型号和2个。模拟两个临床试验，一个F/TAF和F/TDF Prep之一 怀孕和产后的给药，以协助未来的临床试验设计以验证怀孕 - 调整剂量以维持在整个怀孕期间保持非怀孕的HIV保护水平。 这项人群PK研究是迈向前瞻性随机临床试验的关键下一步，以更好地 保护孕妇及其胎儿免受艾滋病毒的收购，并与NICHD母亲一致 小儿传染病分支和艾滋病研究办公室表示“减少 艾滋病毒的发病率和“与预防有关的不良怀孕和婴儿结果”。