Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy

Eric Wenzler, David Butler, Xing Tan, Takayuki Katsube, Toshihiro Wajima, Eric Wenzler, David Butler, Xing Tan, Takayuki Katsube, Toshihiro Wajima

Abstract

Background: The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population.

Objective: The aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations.

Methods: The PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate.

Results: The overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h.

Conclusion: The optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.

Trial registration: ClinicalTrials.gov NCT03032380 NCT02714595 NCT02321800.

Conflict of interest statement

Eric Wenzler serves on the speaker’s bureau for Melinta Therapeutics, Astellas Pharma, and Allergan Plc., and on the advisory board for GenMark Diagnostics and Shionogi & Co., Ltd. Takayuki Katsube is currently an employee of Shionogi & Co., Ltd, and Toshihiro Wajima was an employee of Shionogi & Co., Ltd at the time of this work. David Butler and Xing Tan certify no potential conflicts of interest.

© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Figures

Fig. 1
Fig. 1
Pre-filter plasma concentration-time profiles of cefiderocol during in vitro CVVH and CVVHD at each rate and point of dilution with the HF1400 filter (left) and M150 filter (right). Mean values are displayed with error bars representing standard deviations. CVVH continuous veno-venous hemofiltration, CVVHD continuous veno-venous hemodialysis
Fig. 2
Fig. 2
Individual observed plasma cefiderocol concentration-time profiles for the nine patients receiving CRRT in phase III trials. Each color and symbol combination represents a unique patient (one patient was sampled on days 3 and 9). CRRT continuous renal replacement therapy
Fig. 3
Fig. 3
Individual predicted plasma concentration-time profiles for the nine patients receiving CRRT at optimal effluent flow rate-based dosing regimens (red lines) and the 95% prediction interval of plasma concentrations for patients not undergoing CRRT receiving cefiderocol 2 g every 8 h in phase III trials (gray shaded area). CRRT continuous renal replacement therapy
Fig. 4
Fig. 4
Probability of attaining 75% fT>MIC for patients receiving CRRT and optimal effluent flow rate-based dosing regimens. fT>MIC free time above the minimum inhibitory concentration, CRRT continuous renal replacement therapy, MIC minimum inhibitory concentration, qxh every x hours

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