Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment

Abstract

WCK 5222 is a novel β-lactam-β-lactam-enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative penicillin-binding protein 2 (PBP2) and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogen infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in 48 subjects based on Cockcroft-Gault-estimated creatinine clearance (CL_CR). We enrolled mild (n = 6; CL_CR, 60 to <90 ml/min), moderate (n = 6; CL_CR, 30 to <60 ml/min), and severe (n = 6; CL_CR, <30 ml/min; not on dialysis) impairment, end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CL_CR, ≥90 ml/min). Healthy control subjects and mild and moderate renal impairment subjects received a single 60-min intravenous (i.v.) infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min i.v. infusion of 1.5 g WCK 5222 (1 g FEP plus 0.5 g ZID). Body and renal clearance decreased, and plasma half-life (t_1/2) and the area under the concentration-time curve from time zero extrapolated to infinity (AUC_0-∞ [h µg/ml]) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT02942810.).

Keywords: Acinetobacter baumannii; Enterobacteriaceae; Gram-negative bacterial infections; Pseudomonas aeruginosa; antibacterial agents; bacterial drug resistance; beta-lactamases; chronic kidney disease; drug resistance; multiple drug resistance; pharmacokinetics; pharmacology.

FIG 1

(A) Plasma FEP concentration (conc) versus time. (B) Plasma ZID concentration versus time.

FIG 2

Renal clearance (CL_ren) and systemic clearance (CL_sys) versus CL_CR for FEP and ZID.