| Reference | 1. J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. Epub 2016 Nov 7. <br />
Bruton/’s Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic
Toxicity in Rats. <br />
Erickson RI(1), Schutt LK(2), Tarrant JM(1), McDowell M(1), Liu L(1), Johnson
AR(1), Lewin-Koh SC(1), Hedehus M(1), Ross J(1), Carano RA(1), Staflin K(1),
Zhong F(1), Crawford JJ(1), Zhong S(1), Reif K(1), Katewa A(1), Wong H(1), Young
WB(1), Dambach DM(1), Misner DL(1). <br />
Author information: <br />
(1)Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T.,
M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z.,
K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia,
Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech,
Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
(2)Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T.,
M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z.,
K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia,
Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech,
Inc., 1 DNA Way, MS59, South San Francisco, CA 94080 [email protected]. <br />
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. <br />
|
