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 toxi...Continue Reading
References
Apr 4, 1996·Nature·P CarmelietA Nagy
Apr 4, 1996·Nature·N FerraraM W Moore
Jun 15, 1999·Toxicologic Pathology·A M RyanC A O'Neill
Mar 15, 2001·The New England Journal of Medicine·D J SlamonL Norton
Aug 16, 2002·The New England Journal of Medicine·George D DemetriHeikki Joensuu
May 31, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·B C KuenenH M Pinedo
Jun 5, 2003·Nature Medicine·Napoleone FerraraJennifer LeCouter
Jun 5, 2003·Nature Medicine·Rakesh K Jain
Aug 2, 2003·The New England Journal of Medicine·James C YangSteven A Rosenberg
Jun 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·David H JohnsonFairooz Kabbinavar
Jun 4, 2004·The New England Journal of Medicine·Herbert HurwitzFairooz Kabbinavar
Jul 23, 2004·The New England Journal of Medicine·David CunninghamEric Van Cutsem
Feb 4, 2005·Current Opinion in Gastroenterology·Yan Bi, John A Williams
Jul 15, 2005·The New England Journal of Medicine·Frances A ShepherdUNKNOWN National Cancer Institute of Canada Clinical Trials Group
Jul 25, 2006·Nature Medicine·Risto KerkeläThomas Force
Oct 13, 2006·Current Opinion in Gastroenterology·John A Williams
Oct 19, 2006·Lancet·George D DemetriPaolo G Casali
Dec 29, 2006·The New England Journal of Medicine·Charles E GeyerDavid Cameron
Jan 18, 2007·The Oncologist·Edwin P RockRichard Pazdur
Mar 1, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Laura Q M Chow, S Gail Eckhardt
Apr 24, 2007·Blood·Ehab AtallahJorge Cortes
May 12, 2007·European Urology·Paul C M S Verhagen
Sep 11, 2007·European Urology·Damien Pouessel, Stéphane Culine
Dec 18, 2007·Lancet·Tammy F ChuMing Hui Chen
May 9, 2008·The New England Journal of Medicine·Robert S Kerbel
Jul 4, 2008·Nature Reviews. Cancer·Lee M Ellis, Daniel J Hicklin
Jul 25, 2008·The New England Journal of Medicine·Josep M LlovetUNKNOWN SHARP Investigators Study Group
Nov 5, 2008·Toxicologic Pathology·Shem PatynaWinston Evering
Dec 5, 2008·The New England Journal of Medicine·Giancarlo Spinzi, Silvia Paggi
Feb 23, 2010·The Lancet Oncology·Debashish BoseLee M Ellis
Citations
Mar 19, 2004·Nuclear Medicine and Biology·Thomas BalleLars Farde
Apr 30, 2013·Journal of Pharmaceutical and Biomedical Analysis·Feng ShaoXin Liu
Sep 11, 2012·Journal of Applied Toxicology : JAT·Baichun Yang, Thomas Papoian
Oct 22, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Zhenna XiaGuocai Lu
Dec 6, 2016·International Journal of Environmental Research and Public Health·Xiaofang ZhangGuocai Lu
Oct 15, 2013·Biopharmaceutics & Drug Disposition·Fugang WangKe Liu