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

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 A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs.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.

Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers

“…CL r approximated total CL, as approximately 90% of intravenously administered GSK3342830 was excreted unchanged in urine. The pharmacokinetics observed after single‐ and multiple‐dose administration of GSK3342830 were very similar to those observed for cefiderocol, another parenteral siderophore cephalosporin that is currently in late‐phase development …”

“…A review of manufacturing specifications suggested that contamination (eg, endotoxin or other chemical or adventitial agent) was unlikely. A similar compound in the class recently described adverse reactions traced back to iodide in the drug preparation . Analysis demonstrated that iodide had been appropriately removed during the manufacturing process.…”

“…However, no discernable pattern of cytokine responses was observed differentiating subjects receiving placebo from those receiving active GSK3342830. Recent publication of the healthy volunteer experience from a related antibiotic did not suggest a similar syndrome because of iron chelation in humans …”

Drug delivery systems designed to overcome antimicrobial resistance

“…Cefiderocol also exhibited potent in vivo efficacy against MDR P. aeruginosa in a model of systemic mouse infection . In addition, the pharmacokinetics (PK) safety and tolerability thresholds, ( 21 ) after both single and multiple dosing through intravenous infusion, over a period of 60 minutes in healthy adult subjects, were studied . The results indicate that single and multiple intravenous doses (ranging from 100 up to 2000 mg) were well tolerated in healthy subjects.…”

Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug‐Resistant Pseudomonas aeruginosa: A Case Report

“…Given that β‐lactam resistance in Pseudomonas aeruginosa is typically driven by the presence of efflux pumps, porin channel alterations, or β‐lactamases, cefiderocol’s stability against these three primary resistance mechanisms lends to its promise in the treatment of multidrug‐resistant (MDR) infections due to this organism, as well as those caused by Acinetobacter baumannii, Stenotrophomonas maltophilia, and carbapenem‐resistant Enterobacteriaceae species . Available evidence demonstrates that cefiderocol has a favorable profile with regard to pharmacokinetics, safety, and tolerability . In a phase 2, randomized, double‐blind, noninferiority trial, cefiderocol was noninferior to imipenem‐cilastatin in the treatment of complicated urinary tract infections caused by gram‐negative organisms .…”