Abstract

Objectives

To establish a physiologically based pharmacokinetic (PBPK) model of imipenem, predict its exposure in pediatric patients with different renal function, and optimize the dosing regimen.

Methods

GastroPlus™ was used to construct PBPK models for healthy adults, adults with renal impairment (RI), and children with normal renal function, validated by fold error (<2) between predicted and observed pharmacokinetic parameters. Based on the established PBPK models, the exposure of imipenem in pediatric patients with different renal function was predicted. Monte carlo simulations were used to evaluate the probability of target attainment (PTA) for optimized doses and to determine appropriate dosing regimens for pediatric patients with RI.

Results

The PBPK model could adequately predict the exposure of imipenem in different populations after single and multiple administrations (fold error <2). For 15 mg/kg doses, the AUC of imipenem in children with mild RI, moderate RI and severe RI was 1.05-fold, 1.26-fold, and 2.14-fold that of healthy children, respectively. Prolonging infusion from 30 min to 3 h significantly increased PTA. In addition, for susceptible bacteria with the minimum inhibitory concentration (MIC) < 4 mg/L, the recommended doses for pediatric patients aged ≥ 3 years with normal renal function, mild RI, moderate RI, and severe RI were 15, 15, 12, and 7 mg/kg every 6 hours, respectively, with a 3-hour infusion.

Conclusion

This PBPK model can accurately predict the exposure of imipenem in pediatric patients with renal impairment, and the optimized dosing regimen can meet the pharmacodynamic targets, providing support for the precise use of imipenem.

By Chen Feng, Peng Xiao, Yuchen Qu, Kai Fan, Yueyuan Wang, Xinyun Zhang, Xiaolan Wang, Jie Pan, Yang Deng, Yunli Yu