Advancing Therapeutic Drug Monitoring of oral targeted anticancer drugs: analytical and clinical studies

Abstract

Oral targeted therapies have significantly improved cancer treatment, but variability in drug exposure and narrow therapeutic windows can lead to suboptimal efficacy or increased toxicity. Therapeutic Drug Monitoring (TDM) enables dose optimization by adjusting drug levels based on pharmacokinetic (PK) measurements. This thesis investigates the utility, feasibility of TDM of oral targeted anticancer therapies, and how this could be advanced by the use of home-sampling, contributing to the optimization of patient treatments. In Part 1, the role of TDM was explored through prospective and retrospective studies. The clinical applicability of TDM was assessed for multiple drugs, including lenvatinib, pazopanib, and abiraterone. Real-world data showed that treatment outcomes often differed from clinical trial results, highlighting the need for individualized dosing strategies. In prospective studies it was confirmed that PK-guided dosing successfully reduced subtherapeutic drug exposure in several cohorts. However, for certain drug cohorts routine TDM was deemed unfeasible, due to consistently adequate exposure, too much toxicity or impractical study protocols. Part 2 focused on improving TDM through home-sampling methods. Volumetric absorptive microsampling (VAMS) was analytically and clinically validated as a viable alternative to venous blood collection, with promising results for drugs like imatinib. Patient acceptability was high, and adequate samples were obtained in most cases. However, further validation is required before implementing home-sampling for abiraterone and alectinib. This thesis demonstrated that TDM can optimize treatment outcomes for specific oral targeted anticancer drugs. Home-sampling offers a patient-friendly approach to TDM and could facilitate broader implementation in clinical practice. Future research should focus on refining home-based TDM and expanding its application to additional targeted therapies.