Farag Sheima, Verheijen Remy B, Martijn Kerst J, Cats Annemiek, Huitema Alwin D R, Steeghs Neeltje
Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2017 Mar;56(3):287-292. doi: 10.1007/s40262-016-0439-7.
Low trough imatinib concentration (C ) values have been associated with poor clinical outcomes in gastrointestinal stromal tumour (GIST) patients. This study describes the pharmacokinetics of imatinib in a large cohort of GIST patients in routine clinical care.
An observational study was performed in imatinib-treated GIST patients. Patient and tumour characteristics were derived from the Dutch GIST Registry and medical records. Imatinib concentrations were measured by liquid chromatography with tandem mass spectrometry. The analyses included the occurrence of a low imatinib C (<1000 µg/L), the change in the C over time and the correlation between exposure and response.
In total, 421 plasma samples were available from 108 GIST patients. Most patients (79.6 %) received an imatinib dose of 400 mg. The inter- and intrapatient variabilities in C were 54 and 23 %, respectively. In the first steady-state sample, 44.4 % of patients presented with C values <1000 µg/L; 32.4 % of patients had values <1000 µg/L in >75 % of their samples. Only 33.3 % of patients had C values ≥1000 µg/L in all measured samples. No decrease in C over time was found (P > 0.05). Fifty-seven (91.9 %) of 62 palliative-treated patients had a tumour response (median C 1271 µg/L). Five palliative patients (8.1 %) did not respond (median C 920 µg/L). Given the limited number of non-responders in this cohort, no statistically significant association with clinical benefit could be demonstrated.
In routine clinical care, one third of GIST patients are systematically underexposed with a fixed dose of imatinib. Prospective clinical studies are needed to investigate the value of C -guided imatinib dosing in GIST patients.
伊马替尼谷浓度（C）值较低与胃肠道间质瘤（GIST）患者不良临床结局相关。本研究描述了伊马替尼在一大群接受常规临床治疗的GIST患者中的药代动力学情况。
对接受伊马替尼治疗的GIST患者进行了一项观察性研究。患者和肿瘤特征来自荷兰GIST登记处和病历。伊马替尼浓度通过液相色谱-串联质谱法测定。分析内容包括低伊马替尼C（<1000μg/L）的发生情况、C随时间的变化以及暴露与反应之间的相关性。
共获得108例GIST患者的421份血浆样本。大多数患者（79.6%）接受400mg伊马替尼剂量。C的患者间和患者内变异性分别为54%和23%。在首个稳态样本中，44.4%的患者C值<1000μg/L；32.4%的患者超过75%的样本C值<1000μg/L。仅33.3%的患者所有测量样本的C值≥1000μg/L。未发现C随时间降低（P>0.05）。62例接受姑息治疗的患者中有57例（91.9%）有肿瘤反应（中位C为1271μg/L）。5例姑息治疗患者（8.1%）无反应（中位C为920μg/L）。鉴于该队列中无反应者数量有限，无法证明与临床获益有统计学显著关联。
在常规临床治疗中，三分之一的GIST患者接受固定剂量伊马替尼时系统性暴露不足。需要进行前瞻性临床研究以调查C指导的伊马替尼给药在GIST患者中的价值。
