Determining the Optimal Dosing of Methyldopa in Pregnancy-Induced Hypertension Using PBPK-PD Modeling

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.