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Clinical Trial
, 62 (3)

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

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Clinical Trial

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

Yutaka Saisho et al. Antimicrob Agents Chemother.

Abstract

Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of Cmax and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

Keywords: Gram-negative bacteria; cefiderocol; cephalosporin; pharmacokinetics; siderophores.

Figures

FIG 1
FIG 1
Mean (SD) plasma concentrations of cefiderocol following single-dose administration.
FIG 2
FIG 2
Mean (SD) plasma concentrations of cefiderocol following multiple-dose administration at 0 to 24 h (top) and 216 to 240 h (bottom) after the start of the initial infusion.
FIG 3
FIG 3
Mean (SD) urine concentrations of cefiderocol following single-dose administration.
FIG 4
FIG 4
Mean (SD) fraction of cefiderocol dose excreted in urine following single-dose administration.

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References

    1. Hoban DJ, Reinert RR, Bouchillon SK, Dowzicky MJ. 2015. Global in vitro activity of tigecycline and comparator agents: Tigecycline Evaluation and Surveillance Trial 2004-2013. Ann Clin Microbiol Antimicrob 14:27. doi:10.1186/s12941-015-0085-1. - DOI - PMC - PubMed
    1. Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention, Atlanta, GA: https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.
    1. World Health Organization. 2017. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. World Health Organization, Geneva, Switzerland: http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/.
    1. Livermore DM. 2012. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med 27:128–142. doi:10.3904/kjim.2012.27.2.128. - DOI - PMC - PubMed
    1. Tängdén T, Giske CG. 2015. Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. J Intern Med 277:501–512. doi:10.1111/joim.12342. - DOI - PubMed

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