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

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 (C-minpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUC(DAB)), hydroxy-dabrafenib (AUC(OHD)), and trametinib (AUC(TRA)) 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 AUC(TRA) than the average AUC(TRA) of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91ng/mL center dot h(-1), respectively; p=0.008). Patients who experienced a dabrafenib-related DLT had a higher AUC(DAB) than observed in other patients (9265ng/mL center dot h(-1) vs. 6953ng/mL center dot 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 AUC(DAB) (6990ng/mL center dot h(-1) vs. 9764ng/mL center dot h(-1), p=0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUC(OHD/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 AUC(OHD/DAB)). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.