Drug interactions among the epidermal growth factor receptor inhibitors, other biologics and cytotoxic agents.

The epidermal growth factor receptor (EGFR) signalling pathway is a key element in the growth of several epithelial malignancies. Small molecules tyrosine kinase inhibitors (TKIs) and anti-EGFR monoclonal antibodies (mAbs) prevent the phosphorylation of the receptor, leading to cell cycle arrest at G(1) phase, apoptosis, inhibition of angiogenesis and metastasis. To increase the antitumoral effects of EGFR inhibitors (EGFRIs), a number of combinatory regimens have been evaluated and planned with standard cytotoxic drugs and/or inhibitors of EGFR complementary pathways such as mTOR, VEGF and Ras/Raf/ERK. Compared to EGFRI monotherapy, the combination approach is a promising strategy to improve tumor response and survival. However, pharmacokinetic (absorption, distribution, metabolism and excretion) and pharmacodynamic drug interactions can occur, affecting the outcome. Pharmacokinetics of TKIs can be affected by drugs used in combination: conversely, pharmacokinetic interactions have not been reported for EGFR mAbs. Potential pharmacokinetic interactions occur between EGFRIs and other factors such as food and hydrocarbons in tobacco smoke were also considered. EGFRIs are characterized by a number of pharmacodynamic interactions that must be taken into consideration to avoid adverse events, to increase antitumoral activity, and define potential new strategies for developing efficient combination regimens. In this context, treatment schedule and drug sequence appear to be particularly relevant for combination regimens with EGFRIs. Improved molecular characterisation of the EGFR pathway and its complementary pathways in tumor cells is required to better define predictive pharmacokinetic and pharmacodynamic biomarkers for optimum treatment outcome. 2010 Elsevier Inc. All rights reserved.