Zucchetti M, Pagani O, Torri V, Sessa C, D'Incalci M, De Fusco M, de Jong J, Gentili D, Martinelli G, Tinazzi A
Department of Oncology, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy.
Clin Cancer Res. 1995 Dec;1(12):1517-24.
We aimed to evaluate the pharmacokinetics and pharmacodynamics of etoposide given chronically by the p.o. route to patients with small cell and non-small cell lung cancer. Single daily p.o. doses of 100 mg etoposide were given for 21 consecutive days every 4 weeks to 39 previously untreated patients with small cell lung cancer and 10 patients with non-small cell lung cancer. Bioavailability was studied after one i.v. and one p.o. dose of 100 mg etoposide given 48 h before and on day 1 of treatment, respectively. Etoposide plasma levels were measured using the HPLC method. Inter- and intrapatient variability of the area under the curve of the concentration versus time (AUC) during the first cycle were evaluated using a limited sampling model; the variability of etoposide plasma concentrations (Ecs) during the first cycle was assessed by weekly blood samples taken 24 h after dosing. The overall bioavailability of etoposide (mean +/- SD) was 67% +/- 22% and was not affected by fasting. A much higher inter- than intrapatient variability of both the AUC and 24-h Ec determined on days 8, 15, and 22 was found. Neutropenia was dose limiting and of varying degrees (mean +/- SD of absolute neutrophil count nadir at the first cycle: 1.5 +/- 1.2 x 10(3)/microliter). Neutropenia WHO grade >/=3 occurred in 38% of the patients after the first cycle. Pharmacodynamic analyses showed a significant relationship between the mean 24-h Ec and neutropenia, expressed as log- of absolute neutrophil count nadir or as a relative decrease of neutrophils. A correlation between a critical value of mean 24-h Ec (0.34 microgram/ml) and a high probability of achieving a greater than 80% decrease in absolute neutrophil count was found. Two pharmacodynamic models (one previously described and one developed in this study) were used to evaluate the possibility of predicting neutropenia on the basis of individual etoposide pharmacokinetics and baseline absolute neutrophil count. Pharmacokinetic studies have shown a high interpatient variability and a relatively low intrapatient variability of AUC and 24-h Ec. The application of the pharmacodynamic models and mean 24-h Ec cutoff values has proven statistically valid to predict the occurrence of severe neutropenia. However, it remains to be demonstrated in a prospective manner whether the application of pharmacokinetic/ pharmacodynamic knowledge can improve the overall therapeutic outcome of chronic p.o. treatment with etoposide.
我们旨在评估口服依托泊苷对小细胞肺癌和非小细胞肺癌患者长期给药后的药代动力学和药效学。对39例未经治疗的小细胞肺癌患者和10例非小细胞肺癌患者，每4周连续21天每天口服100mg依托泊苷。分别在治疗前48小时静脉注射100mg依托泊苷一次和治疗第1天口服100mg依托泊苷一次后研究生物利用度。采用高效液相色谱法测定依托泊苷血浆水平。使用有限采样模型评估第一个周期内浓度-时间曲线下面积（AUC）的患者间和患者内变异性；通过给药后24小时采集的每周血样评估第一个周期内依托泊苷血浆浓度（Ecs）的变异性。依托泊苷的总体生物利用度（平均值±标准差）为67%±22%，不受禁食影响。发现在第8、15和22天测定的AUC和24小时Ecs的患者间变异性远高于患者内变异性。中性粒细胞减少是剂量限制性的，且程度不同（第一个周期绝对中性粒细胞计数最低点的平均值±标准差：1.5±1.2×10³/微升）。第一个周期后38%的患者出现WHO≥3级中性粒细胞减少。药效学分析显示平均24小时Ecs与中性粒细胞减少之间存在显著关系，以绝对中性粒细胞计数最低点的对数或中性粒细胞的相对减少表示。发现平均24小时Ecs的临界值（0.34微克/毫升）与绝对中性粒细胞计数下降超过80%的高概率之间存在相关性。使用两种药效学模型（一种先前已描述，一种在本研究中开发）评估基于个体依托泊苷药代动力学和基线绝对中性粒细胞计数预测中性粒细胞减少的可能性。药代动力学研究表明AUC和24小时Ecs的患者间变异性高，患者内变异性相对低。药效学模型和平均24小时Ecs临界值的应用已证明在统计学上可有效预测严重中性粒细胞减少的发生。然而，药代动力学/药效学知识的应用能否改善依托泊苷长期口服治疗的总体治疗结果仍有待前瞻性地证实。
