Development of a Pregnancy-Specific Physiologically Based Pharmacokinetics (PBPK) Model for Aspirin

Aspirin is one of the most commonly used medications in pregnancy, particularly for the prevention of hypertensive disorders. Despite aspirin's widespread use in pregnancy for preeclampsia prevention, its pharmacokinetics (PK) across all trimesters remain poorly characterized, complicating optimal dosing recommendations. To develop a pregnancy-specific physiologically based pharmacokinetic (PBPK) model for aspirin that could be individualized to patient-specific parameters, illustrating differences in aspirin PK across the different trimesters of pregnancy. A PBPK model was developed using GastroPlus (a mechanistically driven simulation software) for nonpregnant and pregnant people at each trimester of pregnancy. The nonpregnant PBPK model was first established and validated against existing data from healthy adult volunteers. Once validated, the model was adapted for pregnant people and verified using observed pharmacokinetic profiles. The simulated PK parameters of aspirin in pregnant and nonpregnant women closely matched the clinical observations reported in the literature, with fold errors ≤ 1.04 (less than 1.5 is considered an acceptable simulation model). The predicted systemic exposure (AUC_0-24h) of salicylic acid (SA), the active metabolite of aspirin decreased throughout gestation, showing a reduction of approximately 20% at 10 weeks and 30% at 40 weeks. An increase in clearance was observed as gestation progressed. The model predicted a modest decrease of 10% in systemic exposure in pregnant women and a 20% increase in fetal exposure to SA as pregnancy progresses. A PBPK model using GastroPlus was developed to describe the PK and pharmacodynamics of aspirin in both pregnant and nonpregnant healthy adults.