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.