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

WCK 5222 is a combination of cefepime and the novel beta-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative 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 grams cefepime/1 gram zidebactam administered as a 1-hour intravenous infusion every 8 hours 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 hours after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over an 8-hour and 10-hour interval following the first and seventh doses, respectively. Penetration ratios were calculated from the AUC_0–8 for plasma, ELF and AM using mean and median concentrations at each BAL sampling time. Plasma C_max and AUC of cefepime and zidebactam increased by 8% to 9% after the seventh versus first dose of WCK 5222. The respective AUC_0-8 values based on mean concentrations for 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_0-8 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.

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