Date of Graduation

5-2016

Document Type

Thesis

Degree Name

Bachelor of Science in Biomedical Engineering

Degree Level

Undergraduate

Department

Biomedical Engineering

Advisor/Mentor

Muldoon, Timothy J.

Committee Member/Reader

Jensen, Hanna

Committee Member/Second Reader

Zaharoff, David A.

Abstract

Drug development makes up a major portion of biomedical engineering research interests. The FDA oversees the introduction, experimentation, and implementation of all drugs before market approval is granted. Even after market approval is granted, the FDA continues to monitor the safety of all drugs. Crizotinib and ceritinib are two anaplastic lymphoma kinase (ALK) inhibitors recently approved by the FDA. Both drugs are indicated for treatment of non-small cell lung cancers (NSCLC) with abnormal ALK gene, and they are approved with a companion diagnostic test that determines ALK abnormality. Clinical trial data suggest that crizotinib and ceritinib can cause liver injury, and this information has been included in the “Warnings and Precautions” section of their labeling. The mechanism of ALK inhibitor induced hepatotoxicity is unknown. This study aimed to observe if crizotinib and ceritinib are directly toxic to liver cells. Primary cultured rat hepatocytes were treated with crizotinib and ceritinib at clinically relevant concentrations for 4, 8 and 24 h, and apoptosis and necrosis were measured. A ~125% to ~150% increase in caspase 3/7 activity was observed at 8 h for ceritinib treated hepatocytes, and significant necrosis (~40%) occurred at 24 h. Ceritinib treated hepatocytes also showed remarkable cytochrome c release at 4 h, the time point when no cell death was detectable. Crizotinib showed no toxicity at 10-fold the maximal blood concentration (Cmax), while ceritinib became toxic at 3-fold Cmax and caused ~40% cell death at 6-fold Cmax, indicating that ceritinib, the second-generation ALK inhibitor, is significantly more toxic than the first-generation drug crizotinib. These data provide novel insights into the mechanisms of ALK inhibitors associated hepatotoxicity.

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