Physiologically Based Pharmacokinetic Modeling to Predict the Exposure and Provide Dosage Regimens of Oseltamivir in Pregnant Women with Comorbid CES1 Polymorphism and Hepatic Cirrhosis

Abstract Oseltamivir (OSE) is widely prescribed for pregnant women with influenza; however, its optimal dosing strategy remains undefined in cases involving carboxylesterase 1 ( CES1 ) gene polymorphism and hepatic cirrhosis. This study aimed to explore OSE dosing regimens for pregnant patients with comorbid CES1 polymorphism and hepatic cirrhosis. A mechanistic physiologically based pharmacokinetic (PBPK) model of OSE was first built and verified in healthy populations, then extrapolated to adult patients with CES1 polymorphism, hepatic cirrhosis, and pregnant patients. The PBPK model successfully predicted and verified the PKs of OSE and its active metabolite oseltamivir carboxylate (OSC) in both non‐pregnant and pregnant women. Simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (C max ) values ranged from 0.5 to 2.0, with the average folding error and absolute average folding error for all concentration–time data points reaching 0.89 and 1.38, respectively. Importantly, for pregnant patients, OSE administration is recommended to be tailored by CES1 genotype, cirrhosis severity, and pregnancy trimester, to achieve post‐dosing AUC levels comparable to those of the non‐pregnant reference population. This integrated pregnancy PBPK model enables us to comprehensively and extensively explore the PK characteristics of OSE and OSC in pregnant women under complex scenarios, thereby providing valuable guidance for clinical applications and precise management of influenza during pregnancy.