Physiologically Based Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Analysis for Ceftriaxone Dosing...

Ceftriaxone is a critical antibiotic for treating severe infections during pregnancy, including community-acquired pneumonia, urinary tract infections, gonorrhea, and syphilis, yet optimal dosing remains undefined due to limited pharmacokinetic data in this population. This study developed and validated a physiologically based pharmacokinetic model for ceftriaxone in pregnant women using the open-source Open Systems Pharmacology Suite. A healthy adult model was first calibrated using data from 193 subjects across multiple studies with doses ranging from 500 to 3000 mg, demonstrating acceptable predictive performance with all simulated-to-observed ratios for maximum concentration (0.60-0.95) and area under the curve (0.64-0.99) falling within accepted 2-fold boundaries. The model was extended to pregnancy by incorporating gestational age-dependent physiological changes, with pregnancy-specific calibration showing excellent agreement (simulated-to-observed ratios of 1.00 for maximum concentration and 0.99 for area under the curve). Population simulations comparing non-pregnant adults to pregnant women at 35 weeks of gestation revealed a 17% reduction in overall exposure and 38% decrease in trough concentrations. Pharmacodynamic target attainment analysis showed that both 1 and 2 g once-daily intravenous regimens maintained 100% $f{T}_{>\mathrm{MIC}}$ against Treponema pallidum (MIC = 0.0025 µg/mL) throughout pregnancy. Nevertheless, the 38% trough reduction translated to a corresponding decrease in the 100% $f{T}_{>\mathrm{MIC}}$ breakpoint (2.81→1.75 µg/mL at 1 g q.d.; 5.61→3.50 µg/mL at 2 g q.d.), quantifying the pharmacodynamic margin under standard regimens. This transparent, reproducible modeling framework provides quantitative support for reconsidering pregnancy dosing strategies and advances precision medicine approaches in obstetric pharmacotherapy during the ongoing maternal syphilis public health crisis.