Physiologically-based pharmacokinetic/pharmacodynamic modeling of meropenem in critically ill patients

Abstract Objectives The purpose of this study was to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients. Methods A PBPK model of meropenem in healthy adults was established using PK-Sim® software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) method were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0−∞, CL to evaluate the accuracy of PBPK model. The model was verified by using meropenem plasma samples obtained from the ICU patients, which were determined by HPLC-MS/MS. The PBPK model was thereafter combined with a PKPD model, developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients. Results The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that we may not need age-specific dose adjustment of meropenem in critically ill patients. Monte Carlo simulations showed that continuous infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4h) was not necessary. Conclusion The PBPK/PD modelling incorporating literature data and prospective study data is able to correctly predict meropenem pharmacokinetics in critically ill patients. Our study provides a reference for realizing clinical personalized medication for critically ill patients.