Single oral dose acute and subacute toxicity of a c-MET tyrosine kinase inhibitor and CDK 4/6 inhibitor combination drug therapy

摘要

c-MET inhibitor, crizotinib, and CDK 4/6 inhibitor, palbociclib, have been evaluated in combination as cancer treatment in vitro. Because the toxicological data for the combination of these drugs is limited, we investigated the toxicity of the crizotinib and palbociclib combination in 80 ICR (CD-1) mice (average age = ~20 weeks). Treatments were arranged as a 2 × 2 × 2 factorial and included sex (female vs. male), crizotinib (0 or 4 mg), and palbociclib (0 or 1 mg). Drugs were administered to mice by oral gavage 24 hours (n = 40) and 7 days (n = 40) prior to the collection of blood and tissue samples to determine serum chemistry, hematology, and histopathology. After dosing, each study group of mice was observed acutely (24 hrs) and subacutely (7 days) for any clinical changes associated with toxicity from the drugs. Serum chemistry, hematological effects, and selected histological tissue samples of each animal immediately after euthanasia were analyzed at the end of the study. No significant abnormalities or changes in the clinical signs, body and organ weight, or gross and histopathological evaluations were observed. Although within the normal reference range, there was an elevation in the red blood cells (P = 0.05) from 24-hour crizotinib- and palbociclib-treated mice (both males and females), which contrasted with the typical anemia observed in palbociclib-treated patients. Administration of the crizotinib and palbociclib combination resulted in an elevation in the ALT liver enzyme (P = 0.05) in the 24-hour treated group (both male and female), but the levels were within the normal ranges of the mice. Overall, serum chemistry and hematology did not reach significant abnormal levels in any of the acute- or subacute-treated groups. The results of this study confirmed that the combination of crizotinib and palbociclib at the given doses did not cause significant treatment-related toxicities in mice.