Physiologically based Pharmacokinetic/Pharmacodynamic Modeling (PBPK/PD) of Famotidine in Pregnancy

Abstract Famotidine, a H 2 ‐receptor antagonist, is commonly used to treat heartburn and gastroesophageal reflux disease during pregnancy. However, information on the pharmacokinetics (PK) of famotidine in pregnant patients is limited since pregnant patients are usually excluded from clinical trials. This study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for famotidine in non‐pregnant and pregnant populations, and to combine it with a pharmacodynamic (PD) model to predict the effect of famotidine on intragastric pH. Clinical data for model evaluation were taken from the literature. The PBPK model successfully predicted famotidine PK in non‐pregnant and pregnant populations. The ratio of predicted versus observed PK parameters in non‐pregnant populations ranged from 0.66 to 1.33 for the area under the concentration–time curve and from 0.50 to 1.27 for peak concentration (C max ). In the pregnant populations, these ratios were 0.94 and 1.17 for early pregnancy, 0.82 and 1.29 for mid‐pregnancy, and 0.72 and 1.06 for late pregnancy, respectively. Compared to the non‐pregnant population, famotidine exposure was predicted to be decreased by, on average, 24% in mid‐pregnancy and 20% in late pregnancy. The PBPK/PD model adequately captured the increase in intragastric pH observed in non‐pregnant adults after famotidine intake and suggested a similar effect in mid‐ and late pregnancy. High inter‐individual variability and minor discrepancies between model predictions and clinical observations indicate a need for further clinical data to reliably inform dosing strategies and therapeutic outcomes for famotidine in pregnant populations.