BRAF和MEK抑制剂是转移性放射性碘（RAI）耐药突变甲状腺癌重分化策略的基石。本研究探讨了达伯非尼和/或曲美替尼治疗患者剂量限制毒性（DLT）起始与暴露-毒性关系，并调查了血浆浓度与RAI再吸收的关联。我们进行了一项回顾性单中心研究，回顾了在我们医院接受肿瘤重分化策略治疗的患者的电子病历，测量了达伯非尼、其活性代谢物羟基达伯非尼和曲美替尼的血浆浓度。通过估计达伯非尼（AUCDAB）、羟基达伯非尼（AUCOHD）和曲美替尼（AUCTRA）的浓度（Cminpred）和总血浆药物暴露（曲线下面积，AUC）。在2014年3月至2021年12月期间，共治疗了22名肿瘤重分化策略患者，其中15名患者纳入了本研究。8名患者（62%）和9名患者（64%）分别出现了达伯非尼或曲美替尼相关的DLT。发生曲美替尼相关DLT的患者的AUCTRA显著高于未出现DLT的患者的平均AUCTRA（分别为390，IQR: 67 vs. 215，IQR: 91 ng/mL.h-1；p = 0.008）。发生达伯非尼相关DLT的患者的AUCDAB高于其他患者的观察值（分别为9265 vs. 6953 ng/mL.h-1；p = 0.09）。没有临床和人口学特征与DLT起始相关。总体而言，15名患者中有9名（60%）显示出肿瘤重分化。RAI再吸收成功的患者的AUCDAB明显低于未成功的患者（分别为6,990 vs. 9,764 ng/mL.h-1；p = 0.014）。此外，达到RAI再吸收的患者的AUCOHD/DAB相对暴露比率显著较高（分别为1.11 vs. 0.71；p = 0.0047）。我们的数据表明，DLT起始与曲美替尼的血浆暴露之间存在关联，以及达伯非尼的血浆暴露（AUC和AUCOHD/DAB比率）与RAI再吸收的关联。这些数据意味着血浆药物监测的应用可能有助于指导重分化治疗的临床实践。

BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI) resistant mutant thyroid cancers. We explored 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. Through concentrations (Cminpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUCDAB), hydroxy-dabrafenib (AUCOHD) and trametinib (AUCTRA) 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 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 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 (6,990 vs. 9,764 ng/mL.h-1, p = 0.014; respectively) compared to patients who did not. Moreover, the relative exposure ratio AUCOHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p = 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 AUCOHD/DAB). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.