Toffoli G, Corona G, Sorio R, Robieux I, Basso B, Colussi A M, Boiocchi M
Division of Experimental Oncology 1, Pharmacology Group, Centro di Riferimento Oncologico, National Cancer Center, Aviano, Italy.
Br J Clin Pharmacol. 2001 Nov;52(5):511-9. doi: 10.1046/j.0306-5251.2001.01468.x.
To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.
A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.
Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01).
Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.
研究口服依托泊苷在实体瘤患者中的群体药代动力学和药效学。
对50例患有各种晚期实体瘤的成年患者进行了一项前瞻性、开放标签、交叉、生物利用度研究。这些患者在第一个周期治疗期间，随机顺序接受口服（100mg胶囊）依托泊苷14天，并在第1天或第7天静脉注射（50mg）依托泊苷。通过高效液相色谱法测定总依托泊苷浓度和游离依托泊苷浓度。使用P-Pharm软件（Simed）估算群体药代动力学参数。血液学毒性和肿瘤反应是主要的药效学终点。
平均清除率为1.14l/h（变异系数25%）。肌酐清除率是唯一能显著降低清除率变异性的协变量（剩余变异系数18%）。（CL = 0.74 + 0.0057CLCR；r² = 0.32）。平均生物利用度为45%（变异系数22%），平均蛋白结合率为91.5%（变异系数5%）。游离的、具有药理活性的依托泊苷暴露量（口服游离AUC）高度可变（平均值2.8mg/l·h；变异系数64%；范围0.4 - 9.5）。它随肌酐清除率增加而降低，随年龄增加而升高，年龄对变异系数的影响占9%。平均口服游离AUC是中性粒细胞减少的最佳预测指标。游离AUC50（使绝对中性粒细胞计数降低50%的暴露量）为1.80mg/l·h。在肺癌患者中，肿瘤有反应的两名患者的口服游离AUC（5.9mg/l·h）高于病情稳定（2.1mg/l·h）或进展性疾病患者（2.3mg/l·h）（P = 0.01）。
长期口服治疗期间游离依托泊苷的暴露量高度可变，是药效学效应的主要决定因素。基于肌酐清除率的群体药代动力学模型对暴露量的预测较差。为了进行剂量个体化或研究暴露量与抗肿瘤效应之间的关系，有必要进行治疗药物监测。
