Single-center evaluation of the pharmacokinetics of WCK 5222 (cefepime-zidebactam combination) in subjects with renal impairment

Richard A. Preston, Grigor Mamikonyan, Stephane DeGraff, James Chiou, Christopher J. Kemper, Allan Xu, Mushtaque Mastim, Ravindra Yeole, Rajesh Chavan, Anasuya Patel, H. David Friedland, Ashima Bhatia

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

WCK 5222 is a novel -lactam–-lactam-enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel -lactam enhancer with a dual action of binding to Gram-negative penicillin-binding protein 2 (PBP2) and -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 g/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.)

Original languageEnglish (US)
Article numbere01484-18
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • Acinetobacter baumannii
  • Antibacterial agents
  • Bacterial drug resistance
  • Beta-lactamases
  • Chronic kidney disease
  • Drug resistance
  • Enterobacteriaceae
  • Gram-negative bacterial infections
  • Multiple drug resistance
  • Pharmacokinetics
  • Pharmacology
  • Pseudomonas aeruginosa

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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