Safety Evaluation of Contezolid (MRX-I) Versus Linezolid in Sprague-Dawley Rats.

Background & objectives: Contezolid (MRX-I) is a novel ortho-fluorophenyl dihydropyridone developed by MicuRx Pharmaceuticals, Inc. It has been approved for the treatment of drug-resistant Gram-positive bacterial infections with relatively lower toxicity than other oxazolidinones such as linezolid. However, the toxicity profile has not yet been completely revealed. The aim of this study was to disclose the toxicity of contezolid in Sprague-Dawley (SD) rats and compare its toxicity profile with linezolid in a standard 4-week toxicity study.

Methods: In this study, SD rats were orally administered with contezolid at doses of 20, 100, or 200/300 mg/kg/day for 28 consecutive days followed by a 28-day recovery period. Linezolid at doses of 100 or 200 mg/kg/day served as a comparator. Clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, and histopathological examinations were conducted.

Results: All females in the 200 mg/kg/day linezolid group were subjected to unscheduled death due to myelosuppression within the first 2 weeks. No abnormalities were noted in the 200 mg/kg/day contezolid group, and the dose level was escalated to 300 mg/kg/day from day 15. Myelosuppression or myelosuppression-associated effects were comparable between the 300-mg/kg/day contezolid group and the 100-mg/kg/day linezolid group. The 'no observed adverse effect level' (NOAEL) of contezolid was determined to be 100 mg/kg/day (with an average AUC_0-24 h of 268.4 μg*h/mL). At the same dose levels, the toxicity of contezolid was significantly lower than that of linezolid.

Conclusion: These findings demonstrate that contezolid exhibits a favorable safety profile compared with linezolid in this 4-week repeated-dose toxicity study in rats.