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Drug Safety

, Volume 36, Issue 7, pp 491–503 | Cite as

Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives

  • Rashmi R. ShahEmail author
  • Joel Morganroth
  • Devron R. Shah
Review Article

Abstract

The introduction of small-molecule tyrosine kinase inhibitors (TKIs) in clinical oncology has transformed the treatment of certain forms of cancers. As of 31 March 2013, 18 such agents have been approved by the US Food and Drug Administration (FDA), 15 of these also by the European Medicines Agency (EMA), and a large number of others are in development or under regulatory review. Unexpectedly, however, their use has been found to be associated with serious toxic effects on a number of vital organs including the liver. Drug-induced hepatotoxicity has resulted in withdrawal from the market of many widely used drugs and is a major public health issue that continues to concern all the stakeholders. This review focuses on hepatotoxic potential of TKIs. The majority of TKIs approved to date are reported to induce hepatic injury. Five of these (lapatinib, pazopanib, ponatinib, regorafenib and sunitinib) are sufficiently potent in this respect as to require a boxed label warning. Onset of TKI-induced hepatotoxicity is usually within the first 2 months of initiating treatment, but may be delayed, and is usually reversible. Fatality from TKI-induced hepatotoxicity is uncommon compared to hepatotoxic drugs in other classes but may lead to long-term consequences such as cirrhosis. Patients should be carefully monitored for TKI-induced hepatotoxicity, the management of which requires individually tailored reappraisal of the risk/benefit. The risk is usually manageable by dose adjustment or a switch to a suitable alternative TKI. Confirmation of TKI-induced hepatotoxicity can present challenges in the presence of hepatic metastasis and potential drug interactions. Its diagnosis in a patient with TKI-sensitive cancer requires great care if therapy with the TKI suspected to be causal is to be modified or interrupted as a result. Post-marketing experience with drugs such as imatinib, lapatinib and sorafenib suggests that the hepatotoxic safety of all the TKIs requires diligent surveillance.

Keywords

Imatinib Sorafenib Sunitinib Gefitinib Erlotinib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Conflict of Interest

The authors have no conflicts of interest that are directly relevant to the content of this review and have not received any financial support for writing it. RRS was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK. JM is the Chief Cardiac Consultant to eResearchTechnology Inc (eRT), Philadelphia, PA, USA which provides cardiac safety services to drug development companies. Both RRS and JM now provide expert consultancy services on development of new drugs to a number of pharmaceutical companies. DRS is a first-year house officer at a district general hospital and has no consultancy relationships.

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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Rashmi R. Shah
    • 1
    Email author
  • Joel Morganroth
    • 2
  • Devron R. Shah
    • 1
  1. 1.Rashmi Shah Consultancy LtdBuckinghamshireUK
  2. 2.eResearch TechnologyPhiladelphiaUSA

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