title: Effects of tyrosine kinase inhibitors on rat isolated heart function and protein biomarkers indicative of toxicity.
abstract: BACKGROUND
  Cardiac toxicity, manifested as diminished contractility, ischemic heart disease, and heart failure is a major issue in drug safety. Concerns revolve around targeted drugs (TKIs) where contractility effects were not anticipated. The ability to predict cardiac toxicity early would help to de-risk drugs in development and prepare physicians to manage risk in the clinic. Issues with current preclinical studies include insufficient testing with informative, translatable models, and predictive biomarkers. The isolated heart model is amenable to multiple assessments which can be combined with current technologies to assess toxicity on a multi-scale level.
  
  
  METHODS
  Rat isolated heart model was used to assess changes in left ventricular (LV) contractility and protein biomarkers BNP, IL6, TNFα, and cardiac troponins T (TnT) and I (TnI). Responses were assessed during perfusion with modified Henseleit Krebs (MHK), and 20 min concentration escalations of verapamil, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), isoproterenol, or 20 min escalations bracketing clinical blood concentrations of sunitinib, sorafenib, and erlotinib. LV parameters and effluent for biomarkers were collected before and during escalating drug concentrations.
  
  
  RESULTS
  Verapamil reduced inotropy with no change in biomarkers, FCCP and isoproterenol reduced and increased heart function respectively and increased TnT and TNFα. Erlotinib had no significant effects on function or biomarkers. Sunitinib diminished function, increased TNFα at 0.1 μM, and increased TnT at higher concentrations. Sorafenib dose dependently increased TNFα beginning at 0.1 μM, reducing contractility and flow rate at 0.6 μM.
  
  
  CONCLUSIONS
  The ex-vivo assay is a sensitive and predictive model for assessing changes in heart function and biomarkers of toxicity and injury. This assay demonstrates the potential for sunitinib and sorafenib to cause cardiac toxicity in humans. Also, TNFα appears to be a biomarker in the heart prior to injury. Due to its versatility, the isolated heart assay has potential to fill gaps in cardiac safety testing early in drug development.
authors: Battelle, 505 King Avenue, Columbus, OH 43210, USA. hendersonk@battelle.org
authors: Kimberly A
authors: KA
authors: Henderson
authors: R Brandon
authors: RB
authors: Borders
authors: John B
authors: JB
authors: Ross
authors: Theresa B
authors: TB
authors: Huwar
authors: Calvin O
authors: CO
authors: Travis
authors: Brandon J
authors: BJ
authors: Wood
authors: Zhenxu J
authors: ZJ
authors: Ma
authors: S Peter
authors: SP
authors: Hong
authors: Thomas M
authors: TM
authors: Vinci
authors: Brian M
authors: BM
authors: Roche
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D009200:Myocardial Contraction / Q000187:drug effects*; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
keywords: Biomarker; Contractility; Erlotinib; FCCP; Isolated heart; Isoproterenol; Rat; Sorafenib; Sunitinib; Verapamil