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.

Abstract

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 0-10mg/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 5mg/kg/day for rats, and undefined for dogs. The treatment resulted in unscheduled mortality in dogs receiving 10mg/kg of SIM010603 or Sunitinib. The adverse effects of SIM010603 on rats and dogs mainly included gastrointestinal toxicity, skeletal toxicity, myelosuppression, thymus atrophy, bronchopneumonia, 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.

• Authors: Yu Mao, Zhenna Xia, Xiaofang Zhang, Ying Zong, Lin Zhu, Bojun Yuan, Guocai Lu
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 50 Issue 5 Pg. 1256-70 (May 2012) ISSN: 1873-6351 [Electronic] England
• PMID: 22343322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Ethylamines
• Indoles
• N-(2-(diethylamino)ethyl)-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indole-3-carboxamide
• Protein Kinase Inhibitors
• Receptor Protein-Tyrosine Kinases

Topics

• Administration, Oral
• Animals
• Dogs
• Dose-Response Relationship, Drug
• Electrocardiography
• Ethylamines (pharmacokinetics, pharmacology, toxicity)
• Female
• Indoles (pharmacokinetics, pharmacology, toxicity)
• Male
• No-Observed-Adverse-Effect Level
• Organ Size (drug effects)
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)