1. Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats
- Author
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Wendy B. Young, Karin Reif, Jed Ross, Jacqueline M. Tarrant, Donna M. Dambach, Karin Staflin, Adam R. Johnson, Arna Katewa, Rebecca Erickson, Maj Hedehus, Shelly Zhong, Sock-Cheng Lewin-Koh, Fiona Zhong, Lichuan Liu, Michelle McDowell, James J. Crawford, Dinah L. Misner, Richard A. D. Carano, Harvey Wong, and Leah Schutt
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Myeloid ,Pyridones ,Inflammation ,Biology ,Gene Expression Regulation, Enzymologic ,Piperazines ,03 medical and health sciences ,Mice ,Dogs ,Species Specificity ,Fibrosis ,medicine ,Acinar cell ,Agammaglobulinaemia Tyrosine Kinase ,Bruton's tyrosine kinase ,Glucose homeostasis ,Animals ,Humans ,Pyrroles ,Pancreas ,Protein Kinase Inhibitors ,Pharmacology ,Dose-Response Relationship, Drug ,Protein-Tyrosine Kinases ,medicine.disease ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Glucose ,Rheumatoid arthritis ,biology.protein ,Cancer research ,Molecular Medicine ,Female ,medicine.symptom ,Tyrosine kinase - Abstract
Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
- Published
- 2016