Introduction

• Crizotinib and pazopanib are oral receptor tyrosine kinase inhibitors (TKIs).
• Crizotinib is used for treatment of locally advanced or metastatic non– small-cell lung cancer (NSCLC); pazopanib is prescribed for metastatic renal cell carcinoma and soft tissue sarcoma.
• In the clinic, serum ALT elevations were observed in 57% of patients (6% had >5X ULN) treated with standard doses of crizotinib {Source: Livertox}.
• In clinical trails of pazopanib, >5X ULN elevations in ALT and bilirubin were observed in only 1-2% of patients {Source: Livertox}.
• In vitro experiments to determine whether these TKIs inhibit bile acid transporters, induce production of reactive oxygen species, and/or inhibit mitochondrial electron transport chain activity were performed.
• DILIsym, a QST model of DILI that incorporates drug/metabolite disposition, multiple mechanistic pathways of DILI (e.g. oxidative
stress, bile acid transporter inhibition, mitochondrial dysfunction), the hepatocyte life cycle, and liver injury biomarkers, was used to assess the potential contribution of each mechanism to the observed toxicity

Ninth American Conference on Pharmacometrics (ACoP) Annual Meeting, October 6-12, 2018, San Diego, CA

By Guncha Taneja, Tamas Szalai, Brett Howell, Scott Siler, Jeffrey L. Woodhead