Toxicities of Receptor Tyrosine Kinase Inhibitors in Cancer Pharmacotherapy: Management with Clinical Pharmacology

Abstract

A number of molecularly targeted anticancer drugs that efficiently inhibit receptor tyrosine kinases, socalled receptor tyrosine kinase inhibitors (TKIs), have been developed. Although these receptor TKIs are generally well tolerated, unexpected toxicities sometimes occur in various organs. TKI-induced adverse events not only lower the quality of life of cancer patients but also reduce dose intensity, and sometimes result in treatment discontinuation. To reduce adverse drug events and increase treatment efficacy, oncologists and clinical pharmacologists have made efforts to establish strategies to treat patients via optimal selection and dosing of TKIs. Drug efficacy and safety are generally determined by the interplay of multiple processes that regulate pharmacokinetics and pharmacodynamics (toxicodynamics). In this review article, we first provide an overview of adverse events caused by receptor TKIs, focusing on gefitinib, erlotinib, sorafenib and sunitinib, followed by a discussion on the association between pharmacokinetics and toxicities induced by these TKIs, with a focus on establishing optimal personalized treatment strategies by controlling pharmacokinetic properties. Finally, we introduce new findings on the molecular mechanisms of TKIinduced toxicities, elucidated using a new strategy, systems toxicology.

Keywords: Receptor tyrosine kinase inhibitor; individualized dosing; interindividual variability; molecular mechanism.; pharmacodynamics; pharmacokinetics; toxicity; toxicodynamics.