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Erlotinib
General information
Tyrosine kinase inhibitors are effective in the targeted treatment of various malignancies. Imatinib was the first to be introduced into clinical oncology, and it was followed by drugs such as erlotinib, gefitinib, sorafenib, sunitinib, and dasatinib. Although they are all competitive inhibitors at the ATP catalytic binding site of tyrosine kinase, they differ from each other in the spectrum of targeted kinases, pharmacokinetics, and adverse effects and adverse reactions [ ].
Erlotinib is used to treat locally advanced non-small-cell lung cancer after failure of at least one prior cytotoxic drug regimen [ ]. It has been used in combination with bevacizumab for non-small-cell lung cancer [ ], mesothelioma [ ], advanced hepatocellular carcinoma [ , ], and recurrent or metastatic squamous-cell carcinoma of the head and neck [ ], and in combination with gemcitabine in the first-line treatment of metastatic pancreatic cancer [ ].
Pharmacokinetics
The absolute systemic availability of erlotinib averages 59% and is significantly increased by a meal. Antacids, proton pump inhibitors, and histamine H 2 receptor antagonists impair the absorption of erlotinib, because its solubility is reduced at pH values exceeding 5.0. More than 90% of a dose is metabolized in the liver, primarily by CYP3A4 and CYP1A2. OSI-420, the major metabolite, has antineoplastic activity. Excretion is mainly via the feces. The half-life averages 36 hours, and steady-state concentrations are reached within 7–8 days. Erlotinib is a potent inhibitor of CYP1A1 and UGT1A1 and a moderate inhibitor of CYP3A4 and CYP2C8.
General adverse effects and adverse reactions
The most common adverse reactions to erlotinib include grade 3/4 rashes and diarrhea, which occur in 9% and 6% of patients respectively, and which warrant drug withdrawal in 1% of patients. Sun protection is generally recommended, because inhibition of EGFR in the skin potentiates the harmful effects of ultraviolet radiation. In patients with lower constitutive concentrations of melanin in the skin, for example Fitzpatrick skin phototypes I and II, higher sensitivity to ultraviolet radiation and a higher probability of more severely graded rash are expected [ ]. Withdrawal of erlotinib has been recommended when signs of new or progressive unexplained pulmonary symptoms are observed, such as dyspnea, cough, and fever, in order to reduce the risk of interstitial lung disease.
Drug studies
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