Variability in bioavailability of small molecular tyrosine kinase inhibitors

• smTKIs generally exhibit a low and variable bioavailability.
• Both pharmaceutical and physiological factors contribute to this.
• Especially solubility and metabolism seem to be essential to the variability.
• Knowledge and consideration of these factors may improve smTKI-therapy.

Small molecular tyrosine kinase inhibitors (smTKIs) are in the centre of the very quickly expanding area of personalized chemotherapy and oral applicability thereof. The number of drugs in this class is rapidly growing, with twenty current approvals by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). The drugs are, however, generally characterized by a poor oral, and thus variable, bioavailability. This results in significant variation in plasma levels and exposure. The cause is a complex interplay of factors, including poor aqueous solubility, issued permeability, membrane transport and enzymatic metabolism. Additionally, food and drug–drug interactions can play a significant role. The issues related with an impaired bioavailability generally receive little attention. To the best of our knowledge, this article is the first to provide an overview of the factors that determine the bioavailability of the smTKIs.