Nonclinical Safety Evaluation of a Transforming Growth Factor β Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs

Anja J Stauber Kelly M Credill
2014 Journal of Clinical Toxicology  
Objective: The transforming growth factor β (TGF-β) pathway regulates diverse cellular functions and plays a prominent role in diseases such as cancer, autoimmune disorders and cardiovascular disease. LY2157299 monohydrate (LY2157299) is a potent and selective inhibitor of TGF-β receptor I kinase that is under clinical evaluation for the treatment of advanced cancer. Methods: This paper characterizes the toxicity profile of LY2157299 in Fischer 344 rats and beagle dogs for up to six months of
more » ... to six months of daily oral dosing. LY2157299 is well tolerated in the rat and dog for up to one month of daily dosing at doses of 150 and 20 mg/kg, respectively. Results: In the rat, LY2157299 is well tolerated after three months of 2 weeks on/2 weeks off intermittent dosing schedule at 50 mg/kg. Chronic (≥3 months) oral administration results in multiple target organ toxicities involving the cardiovascular, gastrointestinal, immune, bone/cartilage, reproductive, and renal systems. Conclusion: Defining the appropriate dose and schedule led to a better understanding of how to define safety margins and thus enable the clinical investigation of LY2157299 in cancer patients.
doi:10.4172/2161-0495.196 fatcat:fwoe7tm27nf6fldyjqf7sx4mmi