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

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 11
• Main Authors: Lepak, Alexander J, Wang, Wen, Andes, David R
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.10.2020
• Subjects: Experimental Therapeutics; polymyxin; Gram negative; MRX-8; pharmacodynamics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01517-20

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 (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 isolate, and the results demonstrated that both (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 (  = 3), (  = 2), (  = 3), and (  = 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 and at 20 to 30. Notably, for and , 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 activity against many different clinically relevant species in both the mouse thigh and lung models.