Cabel Luc, Blanchet Benoit, Thomas-Schoemann Audrey, Huillard Olivier, Bellesoeur Audrey, Cessot Anatole, Giroux Julie, Boudou-Rouquette Pascaline, Coriat Romain, Vidal Michel, Saidu Nathaniel E B, Golmard Lisa, Alexandre Jérome, Goldwasser Francois
Department of Medical Oncology, Cochin Hospital, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.
Paris Descartes University, CARPEM, Paris, France.
Fundam Clin Pharmacol. 2018 Feb;32(1):98-107. doi: 10.1111/fcp.12327. Epub 2017 Nov 10.
Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3-4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUC (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUC and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUC measurement. The majority (60%) of the patients had metastatic renal clear-cell carcinoma (mRCC). Fifty-five (52%) patients experienced grade 3-4 toxicity. Multivariate analysis identified composite AUC as a parameter independently associated with grade 3-4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUC predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6-0.79%; P < 0.0001). At disease progression in patients with mRCC, AUC tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.
治疗药物监测（TDM）可能有助于口服靶向治疗。评估其对治疗管理影响的数据稀少。本研究旨在确定与3 - 4级毒性发生相关的血浆药物暴露阈值，进而确定TDM对临床决策的潜在影响。对接受舒尼替尼治疗的连续门诊患者在第一个周期的第21天至28天进行前瞻性监测，然后每月监测一次直至疾病进展。每次会诊时，测定复合AUC（舒尼替尼 + 活性代谢物SU12662）。将每次会诊时做出的决策与AUC进行匹配，并与基于TDM的决策算法进行比较。共有105例癌症患者和288次会诊与最接近的AUC测量值相匹配。大多数（60%）患者患有转移性肾透明细胞癌（mRCC）。55例（52%）患者出现3 - 4级毒性。多变量分析确定复合AUC是与3 - 4级毒性独立相关的参数（P < 0.0001）。使用ROC曲线，预测≥3级毒性的复合AUC阈值为2150 ng/mL/h（95%CI，0.6 - 0.79%；P < 0.0001）。在mRCC患者疾病进展时，AUC往往低于第一个周期测定的值（分别为1678和2004 ng/mL/h，P = 0.072）。在治疗的第一个周期，TDM可能改变了30%患者的舒尼替尼给药医疗决策，在整个治疗过程中改变了46%患者的决策。TDM常规可行，可能有助于改善毒性管理，并在疾病进展时识别舒尼替尼暴露不足的情况。
