Integrating CRRT as a Virtual Organ Into Physiologically Based Pharmacokinetic Modeling to Optimize Antimicrobial...

Continuous renal replacement therapy (CRRT) extracorporeal drug removal, sepsis-related pathophysiological alterations, and reduced pathogen susceptibility to antimicrobials can lead to treatment failure in septic patients undergoing CRRT, highlighting the urgent need for precision dosing. This study aimed to develop a physiologically based pharmacokinetic (PBPK) modeling framework to characterize antimicrobial pharmacokinetics and support dosing optimization in septic patients undergoing CRRT. Drug-specific PBPK models were established in healthy adults and extrapolated to septic patients by scaling four pathophysiological parameters in PK-Sim. A CRRT compartment was subsequently incorporated in MoBi as a clearance organ and parameterized by modality and intensity to construct a PBPK framework for septic patients undergoing CRRT. Vancomycin, meropenem, and ceftazidime-avibactam were selected as representative antimicrobial agents for model development and validated by graphical comparison with reported data, fold error, and geometric mean fold error (GMFE). The final PBPK model adequately captured the observed data, with predicted area under concentration-time curve and maximum concentration within 0.5-2.0-fold of observed values and GMFE < 2 for all three antimicrobial agents. The validated model simulated pharmacokinetic profiles of 1000 virtual patients across glomerular filtration rate (GFR) values of 0-30 mL/min, five CRRT modalities, and CRRT intensities of 20-40 mL/kg/h, allowing quantification of their relative impact on drug exposure and guiding dosing optimization. The results showed that both GFR and CRRT intensity influenced drug exposure, with GFR showing a greater contribution. Overall, this study provides a quantitative method for predicting antimicrobial exposure and supports model-informed precision dosing in septic patients undergoing CRRT.