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 (CLCR). We enrolled mild (n = 6; CLCR, 60 to <90 ml/min), moderate (n = 6; CLCR, 30 to <60 ml/min), and severe (n = 6; CLCR, <30 ml/min; not on dialysis) impairment, end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR, ≥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 (t1/2) and the area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞ [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.)

Antibiotic resistance breakers: current approaches and future directions

“…A number of phase I clinical trials have been completed investigating the safety, tolerability and pharmacokinetics of zidebactam, both alone (ClinicalTrials.gov, NCT02674347) and in combination with cefepime (ClinicalTrials.gov, NCT02532140 & NCT02707107) (Preston et al . 2019).…”

How to kill Pseudomonas—emerging therapies for a challenging pathogen

“…[147][148][149] The combination was tested in human trials but did not progress beyond phase I. [150][151][152][153] The last combination in clinical development that may have antipseudomonal activity is nacubactam (OP0595/RG6080), a diazabicyclooctane β-lactamase inhibitor similar to the FDA-approved β-lactamase inhibitor, avibactam. In combination with the carbapenem meropenem, it was tested in mouse urinary tract infection (UTI) models against K. pneumoniae, E. coli, and Enterobacter cloacae, but not P. aeruginosa.…”

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

“…139,140) Furthermore, VNRX-5133 restores the antimicrobial activity of cefepime in the presence of NDM-1-producing Enterobacteriaceae. 141) VNRX-5133 has QIDP status and Fast Track designation for the treatment of cUTIs and cIAIs.…”

“…It is being evaluated in phase I clinical trials with QIDP status. 142,143) Zidebactam, a diazabicyclooctane-class non-β-lactam antibiotic bearing a hydrazide moiety, exhibits a dual mechanism of action and high affinity for binding to penicillin-binding protein 2, resulting in the inhibition of Ambler class A and C β-lactamases. [144][145][146][147] Zidebactam also acts as a β-lactam enhancer when combined with cephalosporin.…”