Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?
Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?
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治疗药物监测能否提高伊马替尼治疗 GIST 患者的安全性？
DOI：
10.1002/cam4.1286
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发表时间：
2018-03
期刊：
影响因子：
4
通讯作者：
Wang XD
中科院分区：
文献类型：
--
作者：
Zhuang W;Xie JD;Zhou S;Zhou ZW;Zhou Y;Sun XW;Yuan XH;Huang M;Liu S;Xin S;Su QB;Qiu HB;Wang XD
伊马替尼每天400 mg是CML和GIST患者的标准治疗。血药浓度的互变性非常显著。在许多报告中，良好的治疗效果归因于伊马替尼的足够浓度。然而，很少有研究调查血浆浓度和副作用之间的关系。此外，尚未建立伊马替尼血药浓度检测的浓度上限。本文描述了伊马替尼谷浓度（Cmin）与不良反应（AE）的相关性。血浆样本取自伊马替尼治疗3个月后的患者（稳态，n = 122）。采用液相色谱/串联质谱法测定伊马替尼及其代谢产物NDI的浓度。随着伊马替尼血药谷浓度的增加，骨髓抑制的发生率显著增加。发生骨髓抑制的患者的伊马替尼和NDI血浆水平分别为1698.3 ± 598.6 ng/mL和242.1 ng/mL，显著高于未发生骨髓抑制的患者（1327.2 ± 623.4 ng/mL，P = 1.75 × 10 - 4; 206.3 ng/mL，P = 0.006）。伊马替尼和NDI的估计暴露阈值分别为1451.6 ng/mL和207.1 ng/mL，ROCAUC（95%CI）分别为0.693（0.597-0.789）和0.646（0.546-0.745）。多元回归分析证实了伊马替尼Cmin与骨髓抑制的相关性。其他副作用如液体潴留和皮疹与伊马替尼浓度无关。这些结果表明，应考虑伊马替尼的谷浓度，以增加伊马替尼治疗GIST患者的安全性。
Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (Cmin) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10‐4; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROCAUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROCAUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib Cmin with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.
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