Evaluation of subchronic toxicity of SIM010603, a potent inhibitor of receptor tyrosine kinase, after 28-day repeated oral administration in SD rats and beagle dogs

摘要

SIM010603, a promising multi-targeted receptor tyrosine kinase (RTK) inhibitor, is now being considered for evaluation in phase clinical trial. In this work, the subchronic toxicity of SIM010603 in SD rats and beagle dogs have been characterized. Rats and dogs received SIM010603 orally (0-20 and 0-10 mg/kg/ day, respectively) on a consecutive daily dosing schedule for 28 days following a 14 days recovery period. Sunitinib was used as a positive control. The No Observed Adverse Effect Level (NOAEL) of SIM010603 was 5 mg/kg/day for rats, and undefined for dogs. The treatment resulted in unscheduled mortality in dogs receiving 10 mg/kg of SIM010603 or Sunitinib. The adverse effects of SIM010603 on rats and dogs mainly included gastrointestinal toxicity, skeletal toxicity, myelosuppression, thymus atrophy, broncho-pneumonia, cardiovascular dysfunction, and pancreatic toxicity. Similar observations have also been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets. Most treatment-induced effects were reversible or showed ongoing recovery upon discontinuation of treatment. SIM010603 has shown comparable toxicity effect on beagle dogs, while better tolerability on SD rats when compared to Sunitinib.