Nonclinical toxicities associated with enzastaurin, a potent and specific inhibitor of protein kinase C (PKC), in dogs Free

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Enzastaurin is being developed as a therapy in solid malignant tumors, alone or in combination with chemotherapy or radiation. Enzastaurin, an oral, targeted multi-kinase inhibitor, suppresses signaling through PKCß and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. Enzastaurin has been studied in dogs in repeat-dose toxicity studies of up to 6 months duration. Enzastaurin-related effects identified in dogs include ocular cataracts and hepatobiliary toxicity in a 6-month study and prolongation of the QT interval in a 1-month study.

In a 6 month repeat dose study, non-reversible bilateral lenticular cataracts, identified following 13 weeks of daily oral dosing, were noted in dogs given 200/100 mg/kg. These dogs were orally administered 200 mg/kg daily for 24 days. Due to anorexia and body weight loss, dosing for this group was suspended, the dose was reduced to 100 mg/kg, and dosing was resumed on Day 33. The cataracts were first noted in the posterior capsular region, and, in some animals, progressed over the course of the study to the cortical and nuclear regions of the lens. By the end of the study, cataracts were observed in 5 of 7 males and 6 of 8 females given 200/100 mg/kg.

Hepatobiliary toxicity was noted after 4 weeks of dosing in dogs given 200 mg/kg and was characterized by increased aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. The effects on liver enzyme activities for most of the high-dose dogs were partially to completely reversed following the reduction of the dose to 100 mg/kg. Important histomorphologic changes in the liver included chronic cholangiohepatitis. Hepatobiliary pigment, randomly distributed inflammation, and/or minimal biliary hyperplasia were also noted in this dose group.

At the end of a 1-month repeat dose study, prolongation of the QT interval (the time from the onset of ventricular depolarization [the Q wave] to completion of repolarization [the end of the T wave]) and of the QTc interval (QT interval corrected for heart rate) was noted at 60 mg/kg (the highest dose administered in this study). This finding was not replicated in dogs at higher administered doses (up to and including 200 mg/kg) and higher maximum plasma concentrations in the 6-month repeat-dose toxicity study.

In summary, toxicologically important findings in dogs were limited to irreversible hepatobiliary toxicity and cataracts in dogs given 200/100 mg enzastaurin/kg in a 6-month study and QT/QTc prolongation in dogs given 60 mg enzastaurin/kg in a 1-month study.