Scott Rachel K, Yu Yifan, Marzinke Mark A, Coleman Jenell S, Hendrix Craig W, Bies Robert
Women's Health Research, MedStar Health Research Institute, Washington, DC, United States.
Department of Pharmaceutical Sciences, University of Buffalo, Buffalo, NY, United States.
Front Reprod Health. 2023 Sep 27;5:1224580. doi: 10.3389/frph.2023.1224580. eCollection 2023.
To evaluate upward-adjustment of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) pre-exposure prophylaxis (PrEP) dosing during pregnancy in order to maintain target plasma concentrations associated with HIV protection.
Population pharmacokinetic (PK) modeling and clinical trial simulation (CTS).
We developed population pharmacokinetic models for TFV and FTC using data from the Partners Demonstration Project and a PK study of TDF/FTC among cisgender women by Coleman et al., and performed an in-silico simulation. Pregnancy-trimester was identified as a significant covariate on apparent clearance in the optimized final model. We simulated 1,000 pregnant individuals starting standard daily oral TDF/FTC (300 mg/200 mg) prior to pregnancy. Upon becoming pregnant, simulated patients were split into two study arms: one continuing standard-dose and the other receiving double standard-dose throughout pregnancy.
Standard-dose trough TFV concentrations were significantly lower in pregnancy compared to pre-pregnancy, with 34.0%, 43.8%, and 65.1% of trough plasma concentrations below the lower bound of expected trough concentrations presumed to be the protective threshold in the 1st, 2nd, and 3rd trimesters, respectively. By comparison, in the simulated double-dose group, 10.7%, 14.4%, and 27.8% of trough concentrations fell below the estimated protective thresholds in the 1st, 2nd, and 3rd trimesters, respectively. The FTC trough plasma concentration during pregnancy was also lower than pre-pregnancy, with 45.2% of the steady-state trough concentrations below the estimated protective trough concentrations of FTC. In the pregnancy-adjusted double-dose group, 24.1% of trough plasma concentrations were lower than protective levels.
Our simulation shows >50% of research participants on standard dosing would have 3rd trimester trough plasma TFV concentrations below levels associated with protection. This simulation provides the quantitative basis for the design of prospective TDF/FTC studies during pregnancy to evaluate the safety and appropriateness of pregnancy-adjusted dosing.
评估孕期富马酸替诺福韦二吡呋酯（TDF）/恩曲他滨（FTC）暴露前预防（PrEP）剂量的上调，以维持与HIV防护相关的目标血浆浓度。
群体药代动力学（PK）建模和临床试验模拟（CTS）。
我们利用来自“伙伴示范项目”的数据以及Coleman等人对顺性别女性进行的TDF/FTC PK研究，开发了替诺福韦（TFV）和FTC的群体药代动力学模型，并进行了计算机模拟。在优化后的最终模型中，孕期被确定为影响表观清除率的一个显著协变量。我们模拟了1000名在怀孕前开始每日口服标准剂量TDF/FTC（300mg/200mg）的孕妇。怀孕后，模拟患者被分为两个研究组：一组在整个孕期继续使用标准剂量，另一组在整个孕期接受双倍标准剂量。
与怀孕前相比，孕期标准剂量的TFV谷浓度显著降低，在孕早期、孕中期和孕晚期，分别有34.0%、43.8%和65.1%的血浆谷浓度低于预期谷浓度下限，而该下限被认为是防护阈值。相比之下，在模拟的双倍剂量组中，孕早期、孕中期和孕晚期分别有10.7%、14.4%和27.8%的谷浓度低于估计的防护阈值。孕期FTC的血浆谷浓度也低于怀孕前，45.2%的稳态谷浓度低于FTC估计的防护谷浓度。在孕期调整后的双倍剂量组中，24.1%的血浆谷浓度低于防护水平。
我们的模拟显示，超过50%接受标准剂量治疗的研究参与者在孕晚期的血浆TFV谷浓度会低于与防护相关的水平。该模拟为孕期前瞻性TDF/FTC研究的设计提供了定量依据，以评估孕期调整剂量的安全性和适宜性。
