Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma

摘要

Abstract Introduction Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600 mut metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE. Methods Plasma samples from metastatic BRAFV600 mut melanoma patients treated with dabrafenib ± trametinib were prospectively collected at trough concentration before any dose reduction. Dabrafenib and trametinib were measured by UPLC-MS/MS. Plasma threshold of concentration associated with dose reduction for AE was studied by ROC-curve analysis. Results Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6 ng/ml, mean ± SD 58.7 ± 61.1 ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8 ng/ml, mean ± SD 11.9 ± 4.1 ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6 ng/ml and 33.5 ng/ml respectively ( P 0.0001). Adverse events leading to dabrafenib dose reduction were all grade ≥ 2. No differences in mean trametinib trough plasma concentrations were observed in patients requiring or not dose reduction. A dabrafenib trough plasma threshold of 48 ng/ml can predict the occurrence of adverse events requiring dose reduction. Highlights ? Dabrafenib trough plasma concentrations displayed high interindividual variability. ? A dabrafenib trough plasma threshold of 48 ng/ml can predict adverse events requiring dose reduction. ? Therapeutic drug monitoring may have a potential role to improve safety of dabrafenib. ]]>