Genetic Characterization to Improve Interpretation and Clinical Management of Hepatotoxicity Caused by Tyrosine Kinase Inhibitors

Abstract

Tyrosine kinase inhibitors (TKIs) represent important therapeutic alternatives to, or combinations with, traditional cytotoxic chemotherapy. Despite their selective molecular targeting and demonstrated clinical benefit, TKIs produce a range of serious adverse events, including drug-induced liver injury, that require careful patient management to maintain treatment benefit without harm. Genetic characterization of serious adverse events can identify mechanisms of injury and improve safety risk management. This review presents pharmacogenetic comparisons of two approved TKIs, lapatinib and pazopanib, which reveal different mechanisms of injury and inform the characteristics and risk of serious liver injury in treated patients. The data presented demonstrate the utility of genetic studies to investigate drug-induced liver injury and potentially support its management in patients.

KEYWORDS::

• alanine aminotransferase
• DILI
• Gilbert‘s syndrome
• hemochromatosis
• HLA
• lapatinib
• pazopanib
• total bilirubin
• tyrosine kinase inhibitors
• UGT1A1

Acknowledgements

The authors acknowledge the excellent support of colleagues in Genetics, Oncology Medicines Development, Epidemiology, Drug Metabolism, Safety Assessment and the GlaxoSmithKline Hepatotoxicity Board. In particular, the authors thank N Bing and L Parham for their excellent statistical support of the pharmacogenetic studies with pazopanib and lapatinib, S Landis and JJ Nelson for their tyrosine kinase inhibitor epidemiology studies, and C MacLauchlin, S Castellino and R Brown for their nonclinical investigations. The authors thank the study investigators for their diligence in providing study and case narrative data and the patients for generously providing their clinical data and DNA for these investigations.

Financial & competing interests disclosure

This work was supported by GlaxoSmithKline (GSK). C Spraggs and C-F Xu are employees and stockholders of GSK. CML Hunt was an employee of GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by GlaxoSmithKline (GSK). C Spraggs and C-F Xu are employees and stockholders of GSK. CML Hunt was an employee of GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.