Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Bugnon 17-1, 1011, Lausanne, Switzerland.
Cancer Chemother Pharmacol. 2014 Dec;74(6):1307-19. doi: 10.1007/s00280-014-2599-1. Epub 2014 Oct 9.
This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM).
Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395).
Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml).
This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.
本研究评估了在慢性髓性白血病（CML）患者中，是否可以通过常规的治疗药物监测（TDM）来实现伊马替尼剂量个体化，目标是伊马替尼谷浓度（Cmin）达到 1000ng/ml（耐受范围：750-1500ng/ml），从而改善临床结局，与仅在出现问题时进行 TDM（挽救性 TDM）相比。
伊马替尼浓度监测评估是一项多中心随机对照试验，纳入了接受伊马替尼治疗时间少于 5 年的慢性期或加速期 CML 成年患者。患者以 1:1 的比例随机分配至“常规 TDM”或“挽救性 TDM”。主要终点是 1 年随访时的复合结局（无失败和无毒性的生存并继续接受伊马替尼治疗），采用意向治疗（ISRCTN31181395）进行分析。
在 56 例患者（55 例可评估）中，27 例接受“常规 TDM”的患者中有 14 例（52%）无事件发生，而 28 例接受“挽救性 TDM”的患者中有 16 例（57%）（P=0.69）。在“常规 TDM”组中，14 例患者（中位 Cmin：895ng/ml）正确采用了剂量建议，其不良事件发生率较低（28%），而 13 例未接受建议剂量的患者发生率较高（77%；P=0.03；中位 Cmin：648ng/ml）。
由于患者数量较少，以及处方医生对剂量建议的依从性令人惊讶地有限，本首次目标浓度干预试验无法正式证明“常规 TDM”的益处。然而，在实际选择目标剂量的患者中发现了有利的结局。因此，该研究首次表明 TDM 作为指导药物剂量和调整决策的有用工具。该研究设计和分析为未来针对靶向抗癌药物的随机 TDM 试验提供了一个有趣的范例。
