Population Pharmacokinetics of Amikacin and Monte Carlo Simulation Study in Critically Ill Septic Patients Undergoing Continuous Renal Replacement Therapy with CytoSorb® or oXiris®

Background: Adsorptive devices, including CytoSorb® and oXiris®, are increasingly added to continuous renal replacement therapy (CRRT) in septic patients, but their effect on amikacin clearance and exposure is unknown. We characterized amikacin pharmacokinetics (PK) during adsorptive CRRT and derived dosing implications. Methods: A population PK model was developed in 24 critically ill septic patients (using NONMEM ver. 7.5.0), separating intrinsic clearance (CL_int) from filter-specific extracorporeal clearance (CL_CRRT). Sparse pre-filter sampling was handled using informative priors for distribution parameters. Robustness was assessed by sampling-importance-resampling (SIR) and prediction-corrected visual predictive checks (pcVPC). Monte Carlo simulations (9000 subjects) evaluated probability of target attainment (PTA; Cmax/MIC ≥ 8, AUC24/MIC ≥ 75) and cumulative fraction of response (CFR) against four Gram-negative pathogens across three regimens (500 mg q8h, 500 mg q24h, 1500 mg q24h), two filters, and three connection times. Results: While connected, the CytoSorb® and oXiris® CRRT configurations increased amikacin clearance by 61% and 93%, respectively, accounting for 38–48% of total clearance (CL_TOT). Because these devices were only applied for 10–14 h per 24 h interval in simulated scenarios, there were only minor differences in target attainment. Hence, dosing regimen, not device type or connection timing, dominated. Only amikacin at 1500 mg once daily achieved CFR ≥ 90%, and only for susceptible Enterobacterales. Conclusions: Adsorptive CRRT configurations substantially increase extracorporeal amikacin clearance. These exploratory findings support high-dose, once-daily, concentration-guided amikacin dosing during adsorptive CRRT, although this dose may be insufficient against pathogens with elevated MICs.