Liu Xinyang, Wang Wei, Zhu Jinying, Chen Jingsi, Wang Xiaoyi, Chen Dunjin, Ouyang Defang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China.
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
Clin Pharmacokinet. 2025 Jun 14. doi: 10.1007/s40262-025-01523-2.
Pregnancy-induced hypertension is a significant risk factor for adverse maternal and fetal outcomes, with methyldopa being a commonly prescribed antihypertensive for its safety profile. However, the physiological changes during pregnancy may alter the pharmacokinetics (PK) and pharmacodynamics (PD) of methyldopa, complicating the establishment of optimal dosing regimens.
This study aims to develop and validate a pregnancy-specific physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model for methyldopa to optimize dosing strategies and support individualized treatment plans for managing pregnancy-induced hypertension effectively.
The PBPK-PD model for methyldopa was developed using PK-Sim, MoBi, and MATLAB software, incorporating pregnancy-specific physiological parameters from the literature. The development process involved: (a) constructing and validating a PBPK model for non-pregnant individuals based on intravenous and oral administration, including renal clearance, serum clearance, and enzyme clearance; (b) extending the model to a pregnant PBPK model and validating it for oral administration; (c) constructing a PK/PD model using the maximum effect model; and (d) integrating the PBPK and PK/PD models to form a unified PBPK-PD model. This model was then used to simulate mean arterial pressure (MAP) responses across different stages of pregnancy. Finally, the optimal dosing regimen was calculated.
The model verification results show a good fit, indicating that the parameters are appropriate. The pregnancy model indicated no significant change in phenol sulfotransferase (PST) activity during pregnancy. The physiologically based pharmacokinetic-pharmacodynamic simulations across different stages of pregnancy show fluctuations in both PK and PD; however, these variations are not particularly significant. Ultimately, the results indicate that 500 mg is the optimal dosing regimen for patients with MAP ≤ 130 mmHg. For MAP > 130 mmHg, additional antihypertensive medications are recommended. Due to its delayed onset, methyldopa should be combined with other antihypertensives during the first 48 hours.
The PBPK-PD model developed in this study provides a valuable tool for optimizing methyldopa therapy, supporting personalized treatment strategies, and improving blood pressure management and maternal and fetal health outcomes in pregnancy-induced hypertension.
妊娠高血压是母婴不良结局的重要危险因素，甲基多巴因其安全性常被用作抗高血压药物。然而，孕期的生理变化可能会改变甲基多巴的药代动力学（PK）和药效动力学（PD），使得确定最佳给药方案变得复杂。
本研究旨在开发并验证一种针对甲基多巴的、基于孕期生理的药代动力学 - 药效动力学（PBPK - PD）模型，以优化给药策略，并支持有效管理妊娠高血压的个体化治疗方案。
使用PK - Sim、MoBi和MATLAB软件开发甲基多巴的PBPK - PD模型，并纳入文献中的孕期特定生理参数。开发过程包括：（a）基于静脉和口服给药构建并验证非妊娠个体的PBPK模型，包括肾清除率、血清清除率和酶清除率；（b）将模型扩展为孕期PBPK模型并验证其口服给药情况；（c）使用最大效应模型构建PK/PD模型；（d）整合PBPK和PK/PD模型形成统一的PBPK - PD模型。然后使用该模型模拟孕期不同阶段的平均动脉压（MAP）反应。最后计算最佳给药方案。
模型验证结果显示拟合良好，表明参数合适。孕期模型显示孕期硫酸转移酶（PST）活性无显著变化。孕期不同阶段基于生理的药代动力学 - 药效动力学模拟显示PK和PD均有波动；然而，这些变化并不特别显著。最终结果表明，对于MAP≤130 mmHg的患者，500 mg是最佳给药方案。对于MAP>130 mmHg的患者，建议加用其他抗高血压药物。由于起效延迟，甲基多巴在最初48小时内应与其他抗高血压药物联合使用。
本研究开发的PBPK - PD模型为优化甲基多巴治疗、支持个性化治疗策略以及改善妊娠高血压患者的血压管理和母婴健康结局提供了有价值的工具。
