Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol in Subjects Without Infection and Patients With Complicated Urinary Tract Infection and Acute Uncomplicated Pyelonephritis. (4th October 2017)

• Record Type: Journal Article
• Authors: Katsube, Takayuki; Kawaguchi, Nao; Echols, Roger; Wajima, Toshihiro
• Is Part Of: Open forum infectious diseases. Volume 4(2017)Supplement 1
• Page Start: S522
• Page End: S522
• Publication Date: 2017-10-04
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofx163.1361
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Cefiderocol (also known as S-649266) is a novel parenteral siderophore cephalosporin discovered by Shionogi & Co., Ltd., which exhibits potent efficacy against various Gram-negative bacteria including carbapenem-resistant strains. The aim of this study is to perform a population pharmacokinetic (PK) analysis based on plasma concentrations of cefiderocol in subjects without infection and patients with complicated urinary tract infection (cUTI) (with or without pyelonephritis) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens, and evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationship based on fraction of time for which free drug concentration in plasma exceeds MIC over dosing interval (T f >MIC ). Methods: A population PK analysis was performed using a total of 2571 cefiderocol concentrations in plasma from 91 phase 1 subjects with varying renal function and 238 patients with cUTI or AUP. Covariates were explored from subjects' background data. PK/PD analyses were performed to evaluate the relationship between T f>MIC and clinical, microbiological, and composite (clinical + microbiological) responses in the patients. Results: Plasma concentrations of cefiderocol were adequately described by the developed models. Renal function markers, body weight, and disease status (with or without infection) were significant covariates. Renal function markers were the most influential factors. The post-hoc analyses suggested that the effect of body weight on PK would not be clinically significant. Clearance and volume of distribution of cefiderocol were 26% and 36% higher in patients with infection, respectively, than those in subjects without infection. T f >MIC values were more than 75% in all patients (100% T f >MIC in most patients). The clear PK/PD relationships were not identified for any of efficacy responses. The PK/PD analysis was confounded by high urine concentrations of cefiderocol. Conclusion: Cefiderocol PK would be predictable with renal function markers. The exposure to cefiderocol in patients with infection would be modestly lower than that in subjects without infection. A sufficient exposure to cefiderocol was provided by the tested dose regimens for the patients with cUTI or AUP. Disclosures: T. Katsube, Shionogi & Co., Ltd.: Employee, Salary; N. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary; R. Echols, Shionogi: Consultant, Consulting fee; T. Wajima, Shionogi & Co., Ltd.: Employee, Salary.