Population Pharmacokinetic-Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis®)
Population Pharmacokinetic-Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis®)
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DOI：
10.1007/s40262-012-0011-z
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发表时间：
2012-01-01
影响因子：
4.5
通讯作者：
Jose Perez-Ruixo, Juan
中科院分区：
文献类型：
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作者：
Gonzalez-Sales, Mario;Valenzuela, Belen;Jose Perez-Ruixo, Juan
背景与目的PM 00104（Zeprosis（R））是一种新的海洋衍生化合物，其对多种人类肿瘤细胞系显示出抗肿瘤活性。在I期研究中发现骨髓抑制是PM 00104剂量限制性毒性。本研究的目的是描述肿瘤患者静脉注射PM 00104后中性粒细胞减少的时间过程。方法使用144例接受PM 00104剂量范围为0.053至5 mg/m2的患者的中性粒细胞绝对计数（ANC）和药代动力学数据来估计系统相关的（基线ANC [Circ（0）]、平均通过时间[MTT]、增殖反馈[γ]和成熟反馈[δ]）和药物特异性（来自效应室的一级消除速率常数[k（e0）] [α和β]）参数。根据函数α x C-e（β），假设效应室（C-c）中的浓度降低祖细胞的增殖速率。通过模型评估和模拟，研究了剂量强度、剂量密度和静脉输注时间对严重中性粒细胞减少发生率的影响。Circ（0）、MTT、γ、Δ k（c 0）、α和β的受试者间变异性[%]估计为5.66 x 10（9）个细胞/L（13%），149 h（29%），0.136、0.191、0.00639 h（-1）（32%）、0.332 L/mug（24%）和1.47。年龄、体重、性别、血清白蛋白、总蛋白、肝转移、既往化疗线数和体能状态与模型参数无关。模型评价证明了3级和/或4级中性粒细胞减少症发生率的准确预测。模拟结果表明，PM 00104剂量和给药间隔，但不输注持续时间，是中性粒细胞减少症的严重程度和duration.Conclusions中性粒细胞减少症的时间过程后，PM 00104的主要决定因素，其特征在于模型开发。模型预测的ANC时间进程及其变异性证实中性粒细胞减少症是可逆的、持续时间短且非累积性的。
Background and Objective PM00104 (Zalypsis (R)) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients.Methods Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5 mg/m(2) were used to estimate the system-related (baseline ANC [Circ(0)], mean transit time [MTT], feedback on proliferation [gamma] and maturation [delta]) and drug-specific (first-order elimination rate constant from effect compartment [k(e0)] [alpha and beta]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C-c) were assumed to reduce the proliferation rate of the progenitor cells according to the function alpha x C-e(beta). Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence.Results The typical values (between-subject variability [%]) of the Circ(0), MTT, gamma, delta k(c0), alpha and beta were estimated to be 5.66 x 10(9) cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h(-1) (32 %), 0.332 L/mu g (24 %) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration.Conclusions The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative.