依托泊苷脂质体相关中性粒细胞减少的群体药代动力学-药效学分析。
Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia.
机构信息
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
出版信息
Br J Clin Pharmacol. 2013 Sep;76(3):412-24. doi: 10.1111/bcp.12143.
AIMS
Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia.
METHODS
A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.
RESULTS
Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.
CONCLUSIONS
The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.
目的
盐酸伊立替康是一种微管动力学抑制剂，已被批准用于治疗晚期转移性乳腺癌。中性粒细胞减少症是伊立替康的主要剂量限制不良反应之一。本分析的目的是建立伊立替康相关中性粒细胞减少症的群体药代动力学-药效学模型。
方法
对盐酸伊立替康的 12 项 I、II 和 III 期研究的合并数据集进行了分析。使用先前开发的模型描述伊立替康的群体药代动力学。使用血液学毒性的半生理寿命模型描述伊立替康药代动力学与中性粒细胞减少症之间的关系。使用模拟框架评估了预测对中性粒细胞减少症敏感性增加的患者特征。
结果
1579 例患者的中性粒细胞绝对计数可用。在最终的协变量模型中，基线中性粒细胞计数（ANC0）估计为 4.03×109 个中性粒细胞 l-1[相对标准误差（RSE）为 1.2%]，个体间变异性（IIV，37.3%变异系数[CV%]）。平均转换时间估计为 109 h（RSE 为 1.8%，IIV 为 13.9CV%），反馈常数（γ）估计为 0.216（RSE 为 1.4%，IIV 为 12.2CV%），线性药物效应系数（SLOPE）估计为 0.0451μg l-1（RSE 为 3.2%，IIV 为 54CV%）。白蛋白、天冬氨酸转氨酶和粒细胞集落刺激因子（G-CSF）的接受被确定为 SLOPE 的显著协变量，白蛋白、胆红素、G-CSF、碱性磷酸酶和乳酸脱氢酶被确定为平均转换时间的显著协变量。
结论
该模型可应用于定量研究不同患者群体中性粒细胞减少症的最佳治疗策略。白蛋白被确定为预测中性粒细胞减少时间过程中个体间变异性的最具临床意义的协变量。
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