Development and confirmation of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin in a standardized neutropenic murine pneumonia model
Abstract
BACKGROUND: Murine pneumonia models play a fundamental role in the preclinical development of novel compounds seeking an indication for the treatment of pneumonia. It is vital that plasma exposures in these models are not used as a surrogate for exposure in pulmonary epithelial lining fluid (ELF). Herein, human-simulated regimens (HSRs) in both plasma and ELF of meropenem, cefiderocol and tobramycin are described in the standardized COMBINE murine neutropenic pneumonia model. MATERIALS AND METHODS: HSRs were developed in both plasma and ELF for meropenem and cefiderocol as 2 g q8h 3 h infusions, and tobramycin 7 mg/kg 30 min infusion. Pharmacokinetic studies were performed to confirm plasma and ELF exposures in mice that recapitulated %fT > MIC for meropenem and cefiderocol, and fCmax and fAUC0-24 for tobramycin in humans. RESULTS: Concentration-time profiles and relevant pharmacodynamic exposures for all three compounds were well matched in mice relative to humans. None of the plasma HSRs were able to appropriately humanize the ELF. Thus, modifications of the plasma HSRs were necessary to provide unique HSRs specific to ELF exposure for each compound. CONCLUSIONS: It should not be assumed that lung penetration in mice relative to humans is equivalent. With HSRs confirmed for these three drugs with established clinical use in the treatment of patients with pneumonia, these humanized exposures within the standardized model will allow for back-translation of anticipated…
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