Bioanalysis and clinical pharmacology of tyrosine kinase inhibitors

摘要: Tyrosine kinase inhibitors (TKIs) are recently developed targeted anticancer agents that target molecular abnormalities which unique to cancer cells and, hence, provide an therapy is potentially less toxic healthy cells. Currently, eleven TKIs have been approved for use in several types of cancer. However, considerable inter-individual variability safety and efficacy has observed TKIs. Therefore, there urgent need gain insight into factors involved this large optimal these important novel drugs. One the most determinants may be drug exposure (pharmacokinetics). To able study pharmacokinetics TKIs, methods quantitative analysis their metabolites plasma, sweat tumor tissue were developed. Subsequently, used support clinical studies insights pharmacological aspects various circumstances as instance case specific toxicities, daily practice during PK guided dosing regimens. Despite fact against cells, toxicity TKI treatment shown inevitable. Moreover, severe toxicities lead unavoidable dose modifications or interruptions, a negative impact on efficacy. increase knowledge development skin with sunitinib, occurrence hand foot syndrome (HFS) different seasons was investigated sunitinib secretion patients measured. This generated hypothesis aggravation HFS caused by could possibly limited preventive measures hyperhydrosis future. In unselected outpatient population almost half trough plasma concentrations appeared subtherapeutic risk failure resistance. It not possible predict at based patient- medication related factors. indicated therapeutic monitoring (TDM) paramount should fully implemented routine care identify individual adjusted dosages. As proof concept TDM pilot performed investigate feasibility pharmacokinetically strategy. At standard dose, more than did reach after 14 days therefore, needed adjustments probability effect. Ultimately, third doses, benefit from escalations without causing additional toxicities. implies rather fixed doses would contribute optimization part patients. The hypotheses thesis starting point further research optimize treatment.