Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 8
• Main Authors: Rodvold, Keith A, Gotfried, Mark H, Chugh, Rakesh, Gupta, Mugdha, Patel, Anasuya, Chavan, Rajesh, Yeole, Ravindra, Friedland, H David, Bhatia, Ashima
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-08-2018
• Subjects: Anti-Bacterial Agents; Azabicyclo Compounds; Cefepime; Cephalosporins; Cyclooctanes; Pharmacology; Piperidines; zidebactam; pharmacokinetics; WCK 5222; cefepime; epithelial lining fluid; alveolar macrophages
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.00682-18

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC
) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug (
) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC
values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC
values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.