Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase Inhibitors

__Abstract__ Cancer is the second most common cause of death worldwide after cardiovascular diseases, responsible for an estimated 8.4 million deaths in 2012 and its incidence is still increasing. Through the introduction of many chemotherapeutic agents and hormone treatments in the last decades, treatment options for patients with advanced forms of cancer have improved. Mortality rates have decreased and in some cases cancer is now changing to become a chronic disease. More recent, increased insight in cancer cell biology has led to further improvement in anti-cancer treatment. Much attention has been focused on tyrosine kinases that comprise essential elements of cellular signalling cascades which control proliferation, cell survival and cell death. In cancer, tyrosine kinases can be found activated by mutations, thereby contributing to malignant transformation, tumour growth and metastasis. Targeted therapies, especially tyrosine kinase inhibitors (TKIs), have largely contributed to the recent improvement in anti-cancer treatment. TKIs usually act by competing with adenosine 5’- triphosphate (ATP) for the intracellular ATP binding site of one or more tyrosine kinases. ATP displacement by TKI binding results in inhibition of several processes which are necessary for tumour growth, such as angiogenesis, cell proliferation and cell migration (type I inhibitors). More recently, TKIs have been developed which are non-ATP competitive inhibitors (type II and type III inhibitors). Currently, 17 TKIs are available for the treatment of a broad variety of cancer types, with approval by both the US Food and Drug Administration and European Medicines Agency