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

摘要 口服替诺福韦（TFV）、富马酸二异山梨酯（TDF）和恩曲他滨（F或 FTC）（F/TDF）在妊娠期间推荐给有HIV感染风险的女性。F/替诺福韦艾拉酚胺 由于缺乏疗效数据，富马酸盐（F/TAF）尚未被批准用于顺性别女性的PrEP。尽管 由于艾滋病毒预防在怀孕期间的重要性，孕妇被排除在PrEP功效研究之外。 多项研究表明，不能从非妊娠人群中推断PrEP在妊娠期的疗效 由于肾清除率增加，TFV浓度在第2和第3个妊娠期大幅下降， 分发量。据报告，FTC浓度显著下降，主要是由于 肾排泄与TDF不同，TAF具有最小的肾脏清除率，尽管与TDF相关的其他变化也是如此。 怀孕也可能降低其浓度。 考虑到非妊娠女性达到保护浓度所需的高TFV血液浓度， 在宫颈阴道组织中，需要接近完美地粘附F/TDF以实现HIV保护。减少 在怀孕期间观察到的TFV和FTC浓度引起了人们的关注， 接受F/TDF用于PrEP的孕妇如果不增加剂量，将无法达到保护浓度 加强结构性改革预计F/TAF最终将被批准用于在顺性别妇女中预防艾滋病毒， 评价药物动力学（PK）参数和F/TDF和F/TAF用于PrEP的适当剂量， 怀孕对预防母婴传播至关重要。协助 未来临床试验的设计，以纠正这种可能的剂量不足的F/TDF，并可能，F/TAF，我们 建议探索妊娠期和产后的F/TAF和F/TDF PK参数。我们计划使用 招募非妊娠和妊娠顺性别者的已完成临床研究的F/TDF和F/TAF PK数据 治疗和预防环境中的妇女，包括IMPAACT 1026、CONRAD 137和140、MTN 001、HPTN 066、Partners PrEP、Partners示范项目和几项吉利德PK试验。 我们的具体目标是：1.建立F/TDF和F/TAF相关药物分析物的群体PK模型， 除了人口统计学和生理学变量的变化外，还特别关注与怀孕有关的时间 并建立在现有的PK模型和2.模拟两项临床试验，一项是F/TAF，另一项是F/TDF PrEP 妊娠和产后给药，以协助未来设计临床试验，以验证妊娠- 调整剂量，以维持整个妊娠期的非妊娠HIV保护水平。 这项群体PK研究是前瞻性随机临床试验的关键下一步， 保护孕妇及其胎儿免受艾滋病毒感染，并符合NICHD孕产妇和 儿科传染病分支和艾滋病研究办公室的声明高度优先“减少 艾滋病毒感染率”和“与预防有关的不良妊娠和婴儿结果”。

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”.