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Background: 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. Methods: 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 (Cminpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUCDAB), hydroxy-dabrafenib (AUCOHD), and trametinib (AUCTRA) were estimated. Results: 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 AUCTRA than the average AUCTRA of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h−1, respectively; p = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUCDAB than observed in other patients (9265 ng/mL·h−1 vs. 6953 ng/mL·h−1, respectively; p = 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 AUCDAB (6990 ng/mL·h−1 vs. 9764 ng/mL·h−1, p = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUCOHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p = 0.0047). Conclusions: 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 AUCOHD/DAB). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment. [ABSTRACT FROM AUTHOR]