Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Department of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Leuk Res. 2014 Jul;38(7):764-72. doi: 10.1016/j.leukres.2014.03.023. Epub 2014 Apr 26.
This observational study analyzed imatinib pharmacokinetics and response in 2478 chronic myeloid leukemia (CML) patients. Data were obtained through centralized therapeutic drug monitoring (TDM) at median treatment duration of ≥ 2 years. First, individual initial trough concentrations under 400mg/day imatinib starting dose were estimated. Second, their correlation (Cmin(400mg)) with reported treatment response was verified. Low imatinib levels were predicted in young male patients and those receiving P-gp/CYP3A4 inducers. These patients had also lower response rates (7% lower 18-months MMR in male, 17% lower 1-year CCyR in young patients, Kaplan-Meier estimates). Time-point independent multivariate regression confirmed a correlation of individual Cmin(400mg) with response and adverse events. Possibly due to confounding factors (e.g. dose modifications, patient selection bias), the relationship seemed however flatter than previously reported from prospective controlled studies. Nonetheless, these observational results strongly suggest that a subgroup of patients could benefit from early dosage optimization assisted by TDM, because of lower imatinib concentrations and lower response rates.
本观察性研究分析了 2478 例慢性髓性白血病（CML）患者的伊马替尼药代动力学和疗效。数据通过在中位治疗时间≥2 年时进行集中治疗药物监测（TDM）获得。首先，估计了起始剂量为 400mg/天以下的个体初始谷浓度。其次，验证了它们与报告的治疗反应的相关性（Cmin（400mg））。年轻男性患者和接受 P-gp/CYP3A4 诱导剂的患者预测伊马替尼水平较低。这些患者的反应率也较低（男性 18 个月 MMR 低 7%，年轻患者 1 年 CCyR 低 17%，Kaplan-Meier 估计值）。独立于时间点的多变量回归证实了个体 Cmin（400mg）与疗效和不良事件之间的相关性。可能由于混杂因素（例如剂量调整、患者选择偏倚），但与前瞻性对照研究的报告相比，这种关系似乎较为平坦。尽管如此，这些观察性结果强烈表明，由于伊马替尼浓度较低和反应率较低，辅助 TDM 的早期剂量优化可能使一部分患者受益。
