Neutropenic Rat Thigh Infection Model for Evaluation of the Pharmacokinetics/Pharmacodynamics of Anti-Infectives.

Abstract

The neutropenic mouse infection model is extensively used to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of anti-infective agents. However, it is difficult to evaluate agents following intravenous (i.v.) infusions using this model. Furthermore, in many drug discovery programs, lead identification and optimization is performed in rats, and pharmacology is performed in mice. Alternative models of infection are needed for robust predictions of PK/PD in humans. The rat is an alternative model of infection which can overcome the shortcomings of the mouse model. However, the rat neutropenic thigh infection (NTI) model has not been adequately characterized for evaluation of the PK/PD of anti-infectives. The aim of this study was to characterize the PK/PD of ciprofloxacin against bacterial pathogens in a rat NTI model. We studied the PK/PD relationships of ciprofloxacin against wild-type Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae in neutropenic Wistar rats following administration of 10, 30, and 100 mg/kg as single intravenous boluses and 30- and 60-min infusions. The PK/PD of ciprofloxacin against all four pathogens was AUC/MIC dependent and independent of the duration of administration at 10, 30, and 100 mg/kg. At human-equivalent rat doses, the PK/PD targets of ciprofloxacin achieved in rats for microbiological cure were similar to those reported in human patients. The neutropenic rat thigh infection model can be used to evaluate anti-infective agents intended to be administered as infusions in the clinic, and it complements the mouse model, increasing the robustness of PK/PD predictions in humans. IMPORTANCE Many antibiotics are administered as intravenous infusions in the clinic, especially in intensive care units. Anti-infective drug discovery companies develop clinical candidates that are intended to be administered as i.v. infusions in the clinic. However, there are no well-characterized models with which they can evaluate the PK/PD of the candidates following i.v. infusions. The neutropenic rat thigh infection model reported in this study helps in evaluating anti-infective agents that are intended to be administered as i.v. infusions in the clinic. The rat model is useful for simulating the clinical conditions for i.v. infusions for treatment of infections, such as acute bacterial skin and skin structure, lung, and urinary tract infections. This model is predictive of efficacy in humans and can serve as an additional confirmatory model, along with the mouse model, for determining the proof of concept and for making robust predictions of efficacy in humans.