Bioanalysis and clinical pharmacology of tyrosine kinase inhibitors

Abstract

Tyrosine kinase inhibitors (TKIs) are recently developed targeted anticancer agents that target molecular abnormalities which are unique to cancer cells and, hence, provide an anticancer therapy that is potentially less toxic to healthy cells. Currently, eleven TKIs have been approved for use in several types of cancer. However, considerable inter-individual variability in safety and efficacy has been observed for TKIs. Therefore, there is an urgent need to gain insight into factors that are involved in this large inter-individual variability for optimal use of these important novel drugs. One of the most important determinants for safety and efficacy of TKIs may be drug exposure (pharmacokinetics). To be able to study the pharmacokinetics of TKIs, methods for quantitative analysis of TKIs and their metabolites in plasma, sweat and tumor tissue were developed. Subsequently, these methods were used to support clinical studies to provide insights in pharmacological aspects of TKIs in various circumstances as for instance in case of specific toxicities, in daily practice and during PK guided dosing regimens.

Despite the fact that TKIs are targeted against tumor cells, toxicity of healthy cells during TKI treatment has shown to be inevitable. Moreover, severe toxicities may lead to unavoidable dose modifications or dose interruptions, which have a negative impact on treatment efficacy. To increase knowledge on the development of skin toxicities during therapy with TKI sunitinib, occurrence of hand foot syndrome (HFS) during different seasons was investigated and sunitinib secretion in sweat of patients was measured. This generated the hypothesis that aggravation of HFS is caused by the secretion of sunitinib in sweat and that HFS could possibly be limited by preventive measures for hyperhydrosis in future.

In an unselected outpatient population almost half of the trough plasma concentrations appeared to be subtherapeutic with a risk of treatment failure or development of drug resistance. It was not possible to predict which patients were at risk of subtherapeutic plasma concentrations based on patient- or medication related factors. This indicated that therapeutic drug monitoring (TDM) is paramount and should be fully implemented in routine cancer care to identify patients that are in need of individual adjusted dosages.

As a proof of concept for TDM of sunitinib, a pilot study was performed to investigate the safety and feasibility of the pharmacokinetically guided dosing strategy. At the standard dose, more than half of the patients did not reach target plasma concentrations of sunitinib after 14 days of treatment and, therefore, needed pharmacokinetically guided dose adjustments to increase the probability of a therapeutic effect. Ultimately, a third of the patients that did not reach target sunitinib concentrations at standard doses, did potentially benefit from the implemented dose escalations without causing additional toxicities. This implies that pharmacokinetically guided sunitinib dose escalations rather than fixed doses would contribute to optimization of therapy in a considerable part of the patients.

The insights and hypotheses generated in this thesis could be used as starting point for further research on the pharmacological aspects of TKIs and to further optimize TKI treatment.