Clinical Pharmacology of Kinase Inhibitors in Oncology: Personalized and Optimzed Dosing

Abstract

Kinase inhibitors are an important category of molecularly targeted therapies used for cancer. Verheijen’s doctoral thesis describes several clinical pharmacological studies to optimize and personalize the treatment of cancer with kinase inhibitors, using pharmacokinetics, molecular imaging and biomarkers such as circulating tumor DNA. Most novel kinase inhibitors used at a fixed dose (i.e. a “one size fits all” approach).This thesis shows that clinical application of these agents can be optimized and personalized. For example, dosing of the kinase inhibitor pazopanib could be individualized based on measured plasma concentrations, also known as therapeutic drug monitoring. First bioanalytical methods were developed and validated that enable measurement of pazopanib in patient samples. Then exposure-response analyses were performed to investigate the relation between plasma concentrations and clinical outcomes. Finally, a prospective trial in cancer patients was conducted to demonstrate the safety and feasibility of individualized pazopanib dosing. The case of pazopanib illustrates that individualized dosing, through therapeutic drug monitoring, could be used to optimized and personalized the treatment of cancer with kinase inhibitors.