Pharmacokinetics/Pharmacodynamics of Dabrafenib and Trametinib for Redifferentiation and Treatment of Radioactive Iodine-Resistant Mutated Advanced Differentiated Thyroid Cancer.

BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI)-resistant mutant thyroid cancers. We explored the exposure-toxicity relationship for dose-limiting toxicity (DLT) onset in patients treated with dabrafenib and/or trametinib and investigated whether plasma exposure was associated with RAI reuptake. We conducted a retrospective monocentric study in which we reviewed the electronic medical records of patients treated in our institution with a tumor redifferentiation strategy, for whom plasma concentration of dabrafenib, its active metabolite hydroxy-dabrafenib, and trametinib was measured. Trough concentrations (C) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUC), hydroxy-dabrafenib (AUC), and trametinib (AUC) were estimated. Of the 22 patients treated in a redifferentiation strategy between March 2014 and December 2021, 15 were included in this study. A dabrafenib- or trametinib-related DLT was experienced by 8 (62%) and 9 (64%) patients, respectively. Patients who experienced a trametinib-related DLT exhibited a significantly higher last AUC than the average AUC of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h, respectively;  = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUC than observed in other patients (9265 ng/mL·h vs. 6953 ng/mL·h, respectively;  = 0.09). No clinical and demographical characteristic was associated with the DLT onset. Overall, 9 of 15 (60%) patients demonstrated tumor redifferentiation. Patients in whom RAI reuptake was achieved had significant lower AUC (6990 ng/mL·h vs. 9764 ng/mL·h,  = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUC was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively;  = 0.0047). Our data suggest a relationship between DLT onset and trametinib plasma exposure, as well as an association between achievement of RAI reuptake and dabrafenib plasma exposure (AUC and ratio of AUC). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.