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

摘要 暴露前预防(PrEP)：口服替诺福韦(TFV)、富马酸异丙酚(TDF)和恩曲他滨(F或 对于有感染艾滋病毒风险的妇女，建议在孕期进行(F/TDF)。F/替诺福韦丙氨酰胺 由于缺乏疗效数据，富马酸盐(F/TAF)尚未被批准用于顺性妇女的PrEP。尽管 鉴于孕期预防艾滋病毒的重要性，孕妇已被排除在PrEP疗效研究之外。 正如多项研究表明的那样，不能从非怀孕人群中推断孕前准备的疗效。 TFV浓度在第二和第三个三个月大幅下降，这是因为肾脏清除量增加和 分配量。据报道，联邦贸易委员会浓度的显著下降也主要是由于 肾脏排泄物。与TDF不同，TAF的肾脏清除率很低，尽管与以下相关的其他变化 怀孕也可能会降低它的浓度。 考虑到非怀孕妇女需要较高的TFV血液浓度才能达到保护性浓度 在宫颈阴道组织中，需要近乎完美地遵守F/TDF才能实现艾滋病毒保护。减少的 在怀孕期间观察到的TFV和FTC浓度引起了人们的关注，很大一部分人 如果不增加剂量，服用F/TDF进行PrEP的孕妇将无法达到保护性浓度 调整。鉴于F/TAF最终将被批准用于预防顺性妇女的艾滋病毒， PrEP的药代动力学参数评价及F/TDF和F/TAF的合理剂量 怀孕对于预防孕产妇和围产期传播至关重要。协助，协助 未来的临床试验设计以纠正这种可能的F/TDF剂量不足，并可能纠正F/TAF，我们 探讨妊娠期和产后F/TAF和F/TDF PK参数。我们计划使用 F/TDF和F/TAF PK数据来自纳入非怀孕和怀孕顺性的已完成临床研究 治疗和预防环境中的妇女，包括IMPAACT 1026s、Conrad 137和140、MTN 001、HPTN 066、合作伙伴PrEP、合作伙伴示范项目和几个Gilead PK试验。 我们的具体目标是：1.建立F/TDF和F/TAF相关药物分析物的总体PK模型 除了人口和生理变量的变化外，还特别关注与怀孕相关的时间 并在现有PK模型的基础上，对F/TAF和F/TDF PrEP两种临床试验进行了模拟 在怀孕和产后给药，以帮助未来临床试验的设计，以验证怀孕- 调整剂量，以在整个怀孕期间保持非怀孕艾滋病毒保护水平。 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感染，并符合NICHD孕产妇和 儿科传染病科和艾滋病研究办公室声明的高度优先事项是“减少 艾滋病毒发病率“和”与预防有关的不良妊娠和婴儿结局“。

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”.