A Physiologically Based Pharmacokinetic Model of Ertapenem in Pediatric Patients With Renal Impairment

Ertapenem is a widely used antibiotic; however, its pharmacokinetics has not been fully evaluated in children with renal impairment. A physiologically based pharmacokinetic (PBPK) model of ertapenem was established and validated to simulate its disposition in the healthy population and adults with renal impairment, as well as to predict the exposure in pediatric patients with renal impairment. The simulated PBPK modeling results and the observed data of ertapenem after intravenous administration of various regimens were consistent according to the fold error values of less than 2. Furthermore, %T > MIC of ertapenem was evaluated using the PBPK model. The Cmax was not significantly changed in pediatric patients with renal impairment compared to healthy children. However, the AUC was 1.42-fold, 1.84-fold, 2.37-fold, and 3.52-fold higher in mild, moderate, severe renal impairment, and end-stage renal disease, respectively, than that in healthy children and the doses of ertapenem were reduced to 13 mg/kg b.i.d, 9 mg/kg b.i.d, 6 mg/kg b.i.d, and 5 mg/kg b.i.d, respectively. The probability of achieving 40%T > MIC (MIC ≤ 4 μg/mL) was nearly 100% throughout the recommended dosing interval. In conclusion, our model can be used as a tool to generate better predictions for the most effective ertapenem dosing in pediatric patients.