This study developed and validated a minimal physiologically based pharmacokinetic model (mPBPK) applicable to pregnant women, enabling reasonable prediction of exposure levels for intravenous immunoglobulin (IVIG) and anti-D immunoglobulin (anti-D Ig). The research demonstrates that weight-based dosing strategies can effectively maintain drug exposure levels in pregnant women, providing important reference for pharmacokinetic studies in this population.
Literature Overview
This article, 'Physiologically Based Pharmacokinetic Model for Prediction of Immunoglobulins Exposure in Pregnant Women', published in the journal Antibodies, reviews and summarizes the pharmacokinetic behavior of intravenous immunoglobulin (IVIG) and anti-D immunoglobulin in pregnant women. Since pregnant women are typically excluded from clinical trials, leading to a lack of pharmacokinetic (PK) data, this study integrates pregnancy-specific physiological parameters with allometric scaling approaches to construct a minimal physiologically based pharmacokinetic (mPBPK) model suitable for predicting immunoglobulin exposure in pregnant women.
Background Knowledge
Intravenous immunoglobulin (IVIG) is widely used in the treatment of immune system disorders such as primary humoral immunodeficiency (PID), and also has applications during pregnancy for immune-related conditions like RhD incompatibility. However, pregnant women are often excluded from traditional pharmacokinetic studies, resulting in limited data to support dose adjustments. Anti-D immunoglobulin is primarily used in RhD-negative pregnant women to prevent Rh sensitization. Physiological changes during pregnancy, such as increased plasma volume, weight fluctuations, and altered clearance rates, may affect drug exposure. Additionally, upregulation of FcRn receptor expression in late pregnancy may enhance placental transport of immunoglobulin G (IgG), though the exact mechanisms remain incompletely understood. Due to the lack of a comprehensive whole-body PK model incorporating mechanistic details, this study employed the mPBPK approach using existing physiological parameters and a simplified tissue structure to simulate drug exposure and analyze dose optimization.
Research Methods and Experiments
The study employed a minimal physiologically based pharmacokinetic (mPBPK) model, integrating pregnancy-specific physiological parameters and allometric scaling methods to predict pharmacokinetic exposure of IVIG and anti-D Ig in pregnant women. Model parameters were derived from published studies, with data extracted using the in vitro data extraction tool WebPlotDigitizer. During model development, parameters such as plasma volume, tissue volume, and total lymph flow were dynamically adjusted, and placental and fetal tissues were incorporated into the leaky tissue model. Model validation was performed using an independent PK dataset, calculating average fold error (AFE) and prediction error percentage to evaluate model performance.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides theoretical support for dose optimization of immunoglobulin therapy in pregnant women, demonstrating that the mPBPK model can predict changes in drug exposure and guide weight-based dosing strategies. Future research should incorporate more pregnancy-specific PK data to refine the dynamic description of FcRn receptor changes and improve prediction accuracy. Furthermore, this model can be extended to other monoclonal antibody drugs, facilitating the development of pregnancy-specific therapeutics and enabling personalized treatment approaches.
Conclusion
This study developed and validated a minimal physiologically based pharmacokinetic model (mPBPK) for predicting immunoglobulin exposure during pregnancy. By adjusting pregnancy-specific physiological parameters, the model reasonably predicted pharmacokinetic exposure levels of IVIG and anti-D Ig in pregnant women. The results indicate that weight-based dosing strategies can maintain relatively stable drug exposure in late pregnancy, whereas fixed dosing may lead to significant exposure reductions. This model provides a scientific basis for dose adjustments of antibody drugs during pregnancy, although further refinement with additional clinical data is still required.
