Robert F, Chen S, Miller A A, Lee B C, Molthrop D C, Wheeler R H
Comprehensive Cancer Center, University of Alabama at Birmingham 35294-3300, USA.
Cancer Chemother Pharmacol. 1996;38(5):459-65. doi: 10.1007/s002800050511.
This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer.
A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m2 per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m2 per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables.
Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m2 per day for schedule A and 40 mg/m2 per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was > or = 1 microgram/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r = 0.56, P = 0.003). There were several marginal relationships in schedule B: PS versus Css (r = 0.31, P = 0.058), PS versus AUC (r = -0.38; P = 0.058) and age versus CLp (r = -0.31, P = 0.057).
Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability.
本I期研究旨在评估延长输注依托泊苷的安全性和耐受性，并评估其在晚期癌症患者中的药代动力学/药效学特征。
一组17例患者每21天接受一次依托泊苷7天输注（方案A），剂量为每天30至75mg/m²；另一组37例患者每28天接受一次21天输注（方案B），剂量为每天18至40mg/m²。患者的卡诺夫斯基功能状态（PS）中位数为80%，34例患者既往未接受过化疗。在第一个治疗周期内测定稳态时依托泊苷浓度（Css）和其他药代动力学参数（血浆清除率，CLp；曲线下面积，AUC）。计算相关系数以衡量变量之间的关系。
骨髓抑制是主要毒性反应，与3例死亡相关。方案A因中性粒细胞减少的最大耐受剂量为每天75mg/m²，方案B为每天40mg/m²。两种输注方案患者间药代动力学存在显著差异。尽管依托泊苷剂量水平与血浆水平无显著相关性，但大多数患者的Css≥1μg/ml。仅在方案B中观察到AUC与中性粒细胞绝对减少之间存在显著相关性（r = 0.56，P = 0.003）。方案B中有几个边缘关系：PS与Css（r = 0.31，P = 0.058）、PS与AUC（r = -0.38；P = 0.058）以及年龄与CLp（r = -0.31，P = 0.057）。
总体而言，发现几个血液学变量与依托泊苷剂量水平存在显著相关性，但与Css值无关。在临床实践中应用药效学模型预测血液学毒性的一个主要问题是患者间存在显著差异。
