Graduate Assistant University of Florida Gainesville, Florida, United States
Disclosure(s):
Xinyue Chen: No financial relationships to disclose
Objectives: To develop and evaluate a physiologically based pharmacokinetic (PBPK) model for predicting ceftriaxone exposure in pregnant women, informing potential dosing considerations during pregnancy.
Methods: A PBPK model was developed for healthy adults using PK-Sim, incorporating extensive clinical data for robust validation beyond a previously published PBPK model [1]. The model was then extended to pregnant women by importing individual healthy woman simulations from PK-Sim® to MoBi®, followed by modification to incorporate pregnancy-specific physiological changes. The pregnancy model was calibrated using published ceftriaxone pharmacokinetic data from pregnant women. Additional validation datasets included IV bolus administration data with gestational ages ranging from 28-41 weeks.
Results: The healthy adult PBPK model demonstrated robust predictive performance with strong correlations between simulated and observed values across calibration and validation groups (R² = 0.9435 for AUC0-t; R² = 0.9117 for Cmax). The observed/simulated ratios of AUC0-t and Cmax were within 2-fold of observed values, with 90% of AUC0-t predictions and 78.57% of Cmax predictions were within 1.5-fold of observed values. For pregnant women, preliminary results reveal increases in ceftriaxone clearance compared to non-pregnant women, consistent with observed clinical data. This enhanced clearance appears to be driven by pregnancy-related physiological changes, including increased glomerular filtration rate and altered plasma protein binding, resulting in lower systemic exposure that may necessitate dosing adjustments to maintain therapeutic efficacy.
Conclusions: Our PBPK modeling approach effectively characterized ceftriaxone pharmacokinetics in healthy adults and pregnant women. While results remain preliminary, this framework shows promise for predicting drug exposure in the special population of pregnancy women where traditional clinical studies are challenging. Further model refinement and validation may contribute to optimizing ceftriaxone therapy during pregnancy.
Citations: [1] Alasmari, Fawaz, et al. "Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing." Frontiers in pharmacology 14 (2023): 1200828.
