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

The combination of the c-MET inhibitor crizotinib and the CDK 4/6 inhibitor palbociclib has been explored as a potential cancer treatment in vitro. However, limited toxicological data exist regarding the safety of this drug combination. To address this gap, a study was conducted using 80 ICR (CD-1) mice, with an average age of approximately 20 weeks, to evaluate the toxicity profile of these drugs when administered together. The experimental design followed a 2 × 2 × 2 factorial arrangement, factoring in sex (female vs. male), crizotinib dosage (0 or 4 mg), and palbociclib dosage (0 or 1 mg).

The drugs were administered orally via gavage to the mice, with samples collected at two time points: 24 hours (n = 40) and 7 days (n = 40) post-treatment. Blood and tissue samples were analyzed to assess serum chemistry, hematology, and histopathology. Each group of mice was observed for clinical signs of toxicity both acutely (24 hours) and subacutely (7 days). At the end of the study, serum chemistry, hematological parameters, and histopathological evaluations were conducted for all animals immediately following euthanasia.

No significant abnormalities were observed in clinical signs, body weight, organ weight, or gross and histopathological evaluations across any of the treatment groups. Interestingly, an elevation in red blood cell counts (P = 0.05) was noted in mice treated with the crizotinib and palbociclib combination after 24 hours, contrasting with the typical anemia associated with palbociclib use in human patients. Additionally, a slight but statistically significant increase in the liver enzyme ALT (P = 0.05) was observed in the 24-hour treated group; however, these levels remained within the normal reference range for mice.

Overall, the study found no significant abnormalities in serum chemistry or hematology in either the acute or subacute treatment groups. These findings suggest that the combination of crizotinib and palbociclib, at the tested doses, did not result in significant treatment-related toxicities in mice. This research provides valuable insights into the safety profile of this drug combination, supporting further exploration of its therapeutic potential in preclinical and clinical settings. MSC2530818