Safety pharmacology and toxicology of a novel nitroimidazooxazole antitubercular agent in SD rat and Beagle dogs

Abstract We developed JBD0131, a novel nitroimidazooxazole antitubercular agent, and conducted a comprehensive preclinical evaluation of its safety pharmacology, toxicology, and pharmacokinetics in SD rats and Beagle dogs. JBD0131 was well-tolerated in repeated-dose oral studies, with no treatment-related mortality or significant alterations in organ weights or significant alterations in organ-to-body weight ratios observed. The no-observed-adverse-effect level (NOAEL) was established at 480 mg/kg/day in rats and 300 mg/kg/day in female dogs. In male dogs, the NOAEL was determined to be 15 mg/kg/day, a discrepancy primarily attributed to a slight trend toward Corrected QT interval (QTc) prolongation at higher doses (60 and 300 mg/kg/day) to which males exhibited greater cardiovascular sensitivity. Pharmacokinetic analysis revealed dose-proportional systemic exposure with no accumulation of JBD0131. Although the metabolite DM131 showed moderate accumulation, it was identified as the amino-reduction detoxification product of JBD0131, a conversion that yields a more stable species and is supported by favorable clinical safety data. While Phase I clinical trials of JBD0131 have been reported, this preclinical study remains indispensable as it establishes the toxicological "ceiling" and defines safety margins through supra-therapeutic dosing. By identifying sex-specific sensitivities and clarifying metabolite safety, this work provides a critical scientific foundation for long-term clinical monitoring and risk assessment. Based on indirect comparisons with reported historical data for clinical agents such as bedaquiline and pretomanid, JBD0131 demonstrated a favorable preclinical safety profile in the models tested, supporting its continued development for multidrug-resistant tuberculosis.