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 Tf>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. Tf>MIC values were more than 75% in all patients (100% Tf>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.
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