Berton Mattia, Stader Felix, Bettonte Sara, Battegay Manuel, Marzolini Catia
Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
Faculty of Medicine, University of Basel, Basel, Switzerland.
Open Forum Infect Dis. 2024 Oct 15;11(10):ofae585. doi: 10.1093/ofid/ofae585. eCollection 2024 Oct.
The World Health Organization is pushing to accelerate the study of new human immunodeficiency virus drugs in pregnant women. However, regulatory guidelines do not specify when to conduct pharmacokinetic studies in postpartum women. This knowledge gap carries the potential to jeopardize the outcomes and conclusions of clinical trials aiming to study the effect of pregnancy on drug exposure. We used physiologically based pharmacokinetic (PBPK) modeling along with clinical data to determine the time needed after delivery for drug exposure to return to prepregnancy levels.
A literature review was conducted to collect physiological parameters of pregnant and postpartum women. Regression analyses were performed to derive equations describing the parameters trajectory throughout pregnancy and post partum to inform our PBPK model. Published pharmacokinetic data in pregnant and postpartum women were used for the model verification. The PBPK model was subsequently applied to investigate pharmacokinetic changes throughout pregnancy and post partum.
In agreement with the clinical data the PBPK model was able to describe the different effects of pregnancy on drug exposure, with bictegravir showing the largest reduction in exposure (approximately 50%) during the third trimester while ritonavir and raltegravir showing the lowest (approximately 30%). The successfully verified PBPK model predicted that all evaluated antiretrovirals mostly return to prepregnancy exposure 4 weeks after delivery.
Pharmacokinetic investigations on hepatically cleared drugs should not be conducted before the fifth week after delivery to fully characterize the effect of pregnancy on drug exposure. Because physiological changes remain after delivery, early measurements can underestimate the pregnancy effect on pharmacokinetics, leading to suboptimal dosing recommendations during pregnancy.
世界卫生组织正在推动加快针对孕妇的新型人类免疫缺陷病毒药物的研究。然而，监管指南并未明确何时对产后女性进行药代动力学研究。这一知识空白有可能危及旨在研究妊娠对药物暴露影响的临床试验的结果和结论。我们使用基于生理的药代动力学（PBPK）模型以及临床数据来确定分娩后药物暴露恢复到孕前水平所需的时间。
进行文献综述以收集孕妇和产后女性的生理参数。进行回归分析以得出描述整个孕期和产后参数轨迹的方程，为我们的PBPK模型提供信息。已发表的孕妇和产后女性的药代动力学数据用于模型验证。随后应用PBPK模型来研究整个孕期和产后的药代动力学变化。
与临床数据一致，PBPK模型能够描述妊娠对药物暴露的不同影响，比克替拉韦在孕晚期的暴露减少幅度最大（约50%），而利托那韦和拉替拉韦的暴露减少幅度最小（约30%）。成功验证的PBPK模型预测，所有评估的抗逆转录病毒药物在分娩后4周大多会恢复到孕前暴露水平。
对于经肝脏清除的药物，药代动力学研究不应在分娩后第五周之前进行，以充分表征妊娠对药物暴露的影响。由于分娩后生理变化仍然存在，早期测量可能会低估妊娠对药代动力学的影响，从而导致孕期给药建议不够理想。
