Nonclinical Safety Evaluation of a Transforming Growth Factor ÃÂ² Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs
- *Corresponding Author:
- Anja J Stauber, Ph.D, D.A.B.T
Lilly Corporate CenterEli Lilly and Company
Indianapolis, Indiana 46285, USA
E-mail: [email protected]
Received Date: April 21, 2014; Accepted Date: May 19, 2014; Published Date: May 26, 2014
Citation: Stauber AJ, Credille KM, Truex LL, Ehlhardt WJ, Young JK (2014) Nonclinical Safety Evaluation of a Transforming Growth Factor ß Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs. J Clin Pract 4:196. doi: 10.4172/2161-0495.196
Copyright: © 2014, Stauber AJ,et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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 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.