P-1227. Population Pharmacokinetics (PK) of Cefiderocol (FDC) during Acute Pulmonary Exacerbations (APE) in Adult Persons with Cystic Fibrosis (CF)
Authors: Konig Christina , Monogue Marguerite , Shields Ryan K , Sakon Colleen M , Fratoni Andrew J , Roenfanz Hanna , Finklea James D , Pope Samuel , Nicolau David P , Kuti Joseph L 
Published: January 2025

Abstract

Background
FDC has potent activity against many Gram-negative rods associated with CF APE. Due to metabolic changes seen in CF as well as frequent infection with resistant bacteria, persons with CF (PwCF) frequently have altered PK and may require higher doses. Herein, we describe the population PK and safety of FDC in adult PwCF admitted with an APE.

Methods
Adult PwCF admitted with an APE received at least 3 doses of FDC according to their calculated creatinine clearance (CrCL) by Cockroft-Gault; all doses were infused over 3 hours. Subsequent blood sampling (0, 1.5, 3. 3.25, 3.5, 4, 5, 6,and 8h) was performed after the 3rd - 6th dose. FDC concentrations were analyzed by a validated LC/MSMS method.Protein binding (PB) was determined by ultrafiltration. FDC concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. The free time above the MIC (fT&gt;MIC) for each PwCF was assessed at MICs of 4, 8, and 16 mg/L. Total AUC24h was calculated to compare overall exposures with non-CF patients. Tolerability and adverse events were monitored throughout the study.

Results
Nine PwCF were included; six received 2g q8h and three 2g q6h based on CrCL. The mean (range) age, weight, and CrCL were 33 (22-58) years, 62 (45-78) kg, and 117 (71-164) mL/min, respectively. A two-compartment model best fit the data (AIC 514) with mean estimates for clearance, volume of the central compartment, and inter compartmental transfer constants (K12 and K21) of 5.69 ± 1.45 L/h, 7.42 ± 3.74 L, 2.54 ± 1.76 h-1 and 2.72 ± 3.04 h-1, respectively. PB was 45% (38-51). The 2g q8h regimen for PwCF with CrCL 60-120 mL/min achieved a mean (range) fT &gt; MIC of 100% (100-100), 92% (78-100), and 73% (50-100) at MICs of 4, 8, and 16mg/L, respectively, with AUC24h of 1210 (790-1460) mg/L*h. In those with CrCL &gt;120mL/min, the 2g q6h attained 100% fT&gt; MIC in all PwCF up to 8 mg/L and 83% (71-92) fT &gt; MIC at 16 mg/L, with AUC24h of 1241 (950-1578) mg/L*h. One adverse event of nausea was reported.

Conclusion
Among these 9 PwCF experiencing an APE with normal or augmented renal clearance, FDC using label prescribed dosing regimens according to CrCL was well tolerated and achieved optimal fT &gt;MIC exposure in all patients for pathogens up to MICs of 8mg/L. The AUC24h was also similar to previously reported estimates in non-CF patients.

Disclosures
Christina Konig, PhD, Gilead Inc.: Honoraria|Pfizer Inc.: Honoraria|Shionogi Inc.: Honoraria Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support James D. Finklea, MD, Cystic Fibrosis Foundation: 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 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