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Pancreatic Effects of a Bruton's Tyrosine Kinase Small-molecule Inhibitor in Rats Are Strain-dependent
Manoj Bhaskaran1, Paul D Cornwell1, Steven D Sorden2
11 Eli Lilly and Company, Indianapolis, Indiana, USA.
Abstract:
Inhibitors of Bruton's tyrosine kinase (BTK) are under development as potential therapies for various autoimmune diseases. In repeat-dose toxicity studies, small-molecule BTK inhibitors (BTKi) have been reported to cause a constellation of histologic effects at the pancreatic endocrine-exocrine interface in male rats; however, similar findings were not reported in other species. Since the BTKi-induced pancreatic effect is morphologically similar to well-documented spontaneous changes (predominantly characterized by insular/peri-insular hemorrhage, pigment deposition, chronic inflammation, and fibrosis) that are known to vary by rat strain, we investigated potential strain-dependent differences in the pancreatic effects of a small-molecule BTKi, LY3337641. Following 13 weeks of LY3337641 treatment, Crl:CD(SD) rats were most sensitive, Crl:WI(Han) rats were of intermediate sensitivity, and Hsd:SD rats were least sensitive. These strain differences appear to be related to differences in rate of weight gain across strains and sexes; however, a definitive mechanism was not determined. This study demonstrated that BTKi-induced pancreatic effects were highly dependent on rat strain and correlated with differences in the incidence and severity of the spontaneous background change. When considered with the lack of pancreas effects in nonrat species, these changes in rats are unlikely predictive of similar changes in humans administered a BTK inhibitor.
Insights
Bruton's tyrosine kinase inhibitors (BTKi) can cause pancreatic changes in male rats. These effects are strain-dependent and unlikely to predict human responses, offering insights for drug development.
Area of Science:
- Pharmacology
- Toxicology
- Immunology
Background:
- Bruton's tyrosine kinase (BTK) inhibitors are investigated for autoimmune diseases.
- BTK inhibitors have shown pancreatic effects in male rats, but not other species.
- Spontaneous pancreatic changes in rats vary by strain.
Purpose of the Study:
- To investigate strain-dependent differences in pancreatic effects of a BTK inhibitor (LY3337641).
- To assess the relevance of rat pancreatic findings to human safety.
Main Methods:
- Administered LY3337641 to three different rat strains (Crl:CD(SD), Crl:WI(Han), Hsd:SD) for 13 weeks.
- Evaluated pancreatic histology and correlated findings with spontaneous changes.
- Assessed strain and sex differences in sensitivity.
Main Results:
- Significant strain-dependent differences in sensitivity to LY3337641-induced pancreatic effects were observed.
- Crl:CD(SD) rats were most sensitive, Hsd:SD rats were least sensitive.
- Differences correlated with spontaneous background pancreatic changes and weight gain rates.
Conclusions:
- BTK inhibitor-induced pancreatic effects in rats are highly strain-dependent.
- These findings are unlikely to be predictive of human responses to BTK inhibitors.
- Understanding rat strain differences is crucial for interpreting toxicity data.