Pharmacokinetics and Penetration of a Novel Pharmacodynamically Optimized, Carbapenem-Sparing Antibiotic, WCK 4282 (Cefepime/Tazobactam), into Epithelial Lining Fluid of Healthy, Lung-, and Thigh-Infected Neutropenic Mice.

Abstract

Objectives: Cefepime (FEP), a fourth-generation cephalosporin combined with tazobactam (TAZ), a β-lactamase inhibitor, is being developed by Wockhardt as a pharmacodynamically optimized fixed dose combination (FEP-2 g + TAZ-2 g) for the treatment of multidrug-resistant Gram-negative infections. To undertake an exposure-response analysis for establishing pharmacokinetic (PK)/pharmacodynamic (PD) targets, it is crucial to characterize the PK profile of compounds in surrogate compartments, such as plasma and lung, in clinically relevant animal infection models used to evaluate in vivo efficacy. In the current study, PKs of FEP and TAZ were assessed in plasma and in epithelial lining fluid (ELF) of neutropenic noninfected, lung-infected, and thigh-infected mice. Methods: Neutropenic mice were infected by intranasal or intramuscular administration of 10⁶-10⁷ colony-forming units per milliliter of Escherichia coli to develop infection in lung or thigh. Post 2 hours of infection, single doses of WCK 4282 at 25 + 25, 50 + 50, and 100 + 100 mg/kg were subcutaneously administered. Plasma and bronchoalveolar lavage fluid were collected up to 8 hours post-administration of doses. Results: The PK of FEP and TAZ in plasma/ELF in healthy and infected mice did not differ significantly. The plasma PK profiles of FEP and TAZ were linear and dose proportional with modest ELF penetrations in the neutropenic infected mice. The ELF exposures of FEP and TAZ were slightly lower in thigh-infected mice and higher in lung-infected mice when compared with healthy mice. Irrespective of health condition, the mean ELF/plasma area under the curve penetration ratio for FEP and TAZ was similar and comparable (0.42-0.43). Conclusion: The estimates of FEP and TAZ PK parameters estimated in the current study would help in PK-PD studies for the selection of doses for upcoming in vivo efficacy studies.