Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France.
Département de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Clin Chim Acta. 2017 Sep;472:26-29. doi: 10.1016/j.cca.2017.07.012. Epub 2017 Jul 12.
Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600 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.
Plasma samples from metastatic BRAFV600 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.
Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6ng/ml, mean±SD 58.7±61.1ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8ng/ml, mean±SD 11.9±4.1ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6ng/ml and 33.5ng/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 48ng/ml can predict the occurrence of adverse events requiring dose reduction.
达拉非尼联合曲美替尼治疗 BRAFV600 转移性黑色素瘤患者具有显著疗效，但会出现不良反应（AE），导致 33%的患者需要减少剂量。我们旨在研究血浆中达拉非尼和曲美替尼浓度与 AE 发生之间的关系。
对接受达拉非尼±曲美替尼治疗的转移性 BRAFV600 黑色素瘤患者的血浆样本进行前瞻性采集，在任何剂量减少之前采集谷浓度。采用 UPLC-MS/MS 测定达拉非尼和曲美替尼的浓度。通过 ROC 曲线分析研究与 AE 剂量减少相关的血浆浓度阈值。
共纳入 27 例患者（13 例男性/14 例女性）。达拉非尼的谷血浆浓度显示出高度的个体间变异性，范围为 15.4 至 279.6ng/ml，平均值±标准差为 58.7±61.1ng/ml。谷血浆浓度范围为 4.1 至 23.8ng/ml，平均值±标准差为 11.9±4.1ng/ml。需要减少剂量的 AE 患者的平均谷血浆浓度明显高于其他患者：分别为 118.6ng/ml 和 33.5ng/ml（P<0.0001）。导致达拉非尼剂量减少的不良反应均为≥2 级。需要或不需要剂量减少的患者的平均曲美替尼谷血浆浓度无差异。达拉非尼谷血浆浓度阈值为 48ng/ml 可预测需要剂量减少的不良反应的发生。
