Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Abstract

AbstractCefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug–drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.