Development of a Sensitive Plasma Lenvatinib Quantification Method and Validation in Thyroid Cancer Patients

Context Lenvatinib (LEN) is effective in the treatment of radioactive iodine refractory differentiated thyroid cancer (DTC), though it is associated with frequent and potentially severe adverse event (AEs). The dose dependency of LEN-related toxicity remains unclear, since no data are available on this topic. Objective This study aimed to investigate the relationship between LEN dose and plasma concentrations in real-life patients by a novel and validated method for quantifying LEN in plasma samples. Design and setting A sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) assay for LEN quantification in plasma was set-up, with a wide analytical range (0.7-500 ng/mL). Consecutive plasma samples from 19 patients with radioactive iodine-refractory, metastatic DTC were analyzed. Results A positive correlation between the administered LEN dose and plasma concentrations was found, particularly in patients on low doses (<18 mg daily). Linear mixed-effects models (LMMs) demonstrated significant inter-individual variability in plasma LEN concentrations, contributing to 17-28% of the total variance. This variability was more pronounced at higher doses (≥18 mg), being more likely the consequence of LEN-related AEs than of a dose-dependent effect. Conclusions This is the first real-life evaluation of inter-individual LEN pharmacokinetics variability in advanced DTC patients, obtained by means of the new developed HPLC-MS/MS method. Our results suggest that the dose-response relationship of LEN in radioactive iodine-refractory DTC may be more complex than previously understood, with substantial inter-patient variability and dose-dependent effects. Further studies are needed to determine the implications of our findings in the clinical management of these patients.