Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models against Gram-Negative Pathogens

Lepak Alexander J.; Wang Wen; Andes David R.

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Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models against Gram-Negative Pathogens

机译：Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models against Gram-Negative Pathogens

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MRX-8 is a novel polymyxin analogue in development for the treatment of infections caused by Gram-negative pathogens, including those resistant to other antibiotic classes. In the present study, we examined the pharmacodynamic activity of MRX-8 against a variety of common Gram-negative pathogens in the neutropenic mouse thigh and lung models. Additionally, we examined polymyxin B (PMB) as a comparator. Plasma pharmacokinetics of MRX-8 and PMB were linear over a broad dosing range of 0.156 to 10 mg/kg of body weight and had similar AUC(0-infinity) (area under the drug concentration-time curve from 0 h to infinity) exposures of MRX-8, 0.22 to 12.64 mg . h/liter, and PMB, 0.12 to 13.22 mg . h/liter. Dose fractionation was performed for MRX-8 using a single Escherichia coli isolate, and the results demonstrated that both C-max (maximum concentration of drug in serum)/MIC and AUC/MIC ratios were strongly associated with efficacy. In the thigh model, dose-ranging studies included strains of E. coli (n = 3), Pseudomonas aeruginosa (n = 2), Klebsiella pneumoniae (n = 3), and Acinetobacter baumannii (n = 1). Both MRX-8 and PMB exhibited increased effects with increasing doses. MRX-8 and PMB free AUC/MIC exposures for net stasis were similar for E. coli and K. pneumoniae at 20 to 30. Notably, for P. aeruginosa and A. baumannii, the free AUC/MIC ratio for stasis was numerically much smaller for MRX-8 at 6 to 8 than for PMB at 16 to 37. In the lung model, MRX-8 was also more effective than PMB when dosed to achieve similar free-drug AUC exposures over the study period. MRX-8 is a promising novel polymyxin analogue with in vivo activity against many different clinically relevant species in both the mouse thigh and lung models.

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《Antimicrobial agents and chemotherapy.》 |2020年第11期|共11页
作者
Lepak Alexander J.; Wang Wen; Andes David R.;
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作者单位

MicuRx Pharmaceut, Foster City, CA USA;

Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53726 USA;

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正文语种英语
中图分类治疗学;
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MRX-8; polymyxin; pharmacodynamics; Gram negative;

Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models against Gram-Negative Pathogens

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