Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy

In this report, we describe our scientific approach for including effluent flow rate (Q_E )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CL_nonrenal ) and extracorporeal clearance by CRRT (CL_CRRT ), based on the following rationale: (a) The renal clearance (CL_renal ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CL_nonrenal represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CL_CRRT was estimated by the product of unbound (free) fraction of plasma drug concentration (f_u ) and Q_E because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CL_nonrenal  + f_u  × Q_E . Accordingly, the cefiderocol dosing regimens for patients receiving CRRT in clinically relevant ranges of Q_E were determined with the goal of achieving an average daily area under the concentration-time curve (AUC) observed in patients not receiving CRRT. Subsequently, pharmacokinetic (PK) simulations demonstrated that cefiderocol PK profiles following the Q_E -based dosing in patients receiving CRRT would be similar to those in patients not receiving CRRT.