P-1217. Validation of Cefiderocol (FDC) Package Insert Dosing Recommendation for Patients receiving Continuous Renal Replacement Therapy (CRRT): A Prospective Multi-Center Pharmacokinetic Study
Authors: Fouad Aliaa , Kobic Emir , Nicolasora Nelson P , Thompson Bastin Melissa L , Adams Paul M , Shen Yuwei , Fratoni Andrew J , Ye Xiaoyi , Kuti Joseph L , Nicolau David P , Asempa Tomefa E 
Published: January 2025

Abstract

Background
FDC is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving CRRT including modalities such as continuous venovenous hemodiafiltration (CVVHDF). The objective of this study was to investigate the population pharmacokinetics of FDC among patients receiving CRRT and validate these novel dosing recommendations.

Methods
A multicenter pharmacokinetic study among critically ill patients receiving CRRT was conducted. Subsequent blood sampling was performed at steady-state, and FDC concentrations were assayed by a validated Liquid Chromatography with tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R. The free time above the minimum inhibitory concentration (fT&gt;MIC) was calculated with a target of ≥75% fT &gt;MIC associated with clinical success. Total daily area under the concentration time curve (AUCdaily) was used as a surrogate for safety and tolerability.

Results
Fourteen patients on CVVHDF renal support were enrolled from August 2022 until December 2023; Hartford Hospital (n=7), Banner University Medical Center (n=5), and University of Kentucky Medical Center (n=2). Average age was 55 years and majority were male (n=9). Mean body weight was 113.5 kg, and effluent flow rates ranged from 2.1 to 5.1 L/h. FDC concentrations best fitted a two-compartment model. Mean ± SD parameter estimates for clearance, volume of the central compartment, and intercompartment transfer constants (K12 and K21) were 3.5 ± 1.5 L/h, 10.7 ± 8.4 L, 3.9 ± 1.8 h-1, and 2.2 ± 2.2 h-1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT &gt;MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg*h/ L (Table 1). FDC was well tolerated with no serious adverse events reported among these critically ill patients.

Conclusion
Based on these data, the current package insert dosing recommendations resulted in pharmacodynamically optimized FDC exposures. The simulated concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily were within the range observed in patients not receiving CRRT in the Phase 3 clinical trials, suggestive of a safe and therapeutic profile.

Disclosures
Emir Kobic, BCIDP, Shionogi: Grant/Research Support|Shionogi: Speaker Bureau Melissa L. Thompson Bastin, PharmD, PhD, Baxter Healthcare: Advisor/Consultant|Baxter Healthcare: Board Member|Fresenius: Advisor/Consultant Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support Xiaoyi Ye, MD, Sanofi: Advisor/Consultant Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Tomefa E. Asempa, PharmD, FDA/CDER: Grant/Research Support|Paratek: Grant/Research Support|Shionogi: Grant/Research Support|Spero: Grant/Research Support|VenatoRx: Grant/Research Support