Fogli S, Danesi R, De Braud F, De Pas T, Curigliano G, Giovannetti G, Del Tacca M
Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy.
Ann Oncol. 2001 Nov;12(11):1553-9. doi: 10.1023/a:1013133415945.
Gemcitabine and paclitaxel are two of the most active agents in non-small-cell lung cancer (NSCLC), and pharmacologic investigation of the combination regimens including these drugs may offer a valuable opportunity in treatment optimization. The present study investigates the pharmacokinetics and pharmacodynamics of paclitaxel and gemcitabine in chemotherapy-naive patients with advanced NSCLC within a phase I study.
Patients were given i.v. paclitaxel 100 mg/m2 by one-hour infusion followed by gemcitabine 1,500, 1,750 and 2,000 mg/m2 by 30-min administration. Plasma levels of paclitaxel, gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) were determined by high-performance liquid chromatography (HPLC). Concentration-time curves were modeled by compartmental and non-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD) relationships were fitted according to a sigmoid maximum effect (Emax) model.
Paclitaxel pharmacokinetics did not change as a result of dosage escalation of gemcitabine from 1,500 to 2,000 mg/m2. A nonproportional increase in gemcitabine peak plasma levels (Cmax, from 18.56 +/- 4.94 to 40.85 +/- 14.85 microg/ml) and area under the plasma concentration-time curve (AUC, from 9.99 +/- 2.75 to 25.01 +/- 9.87 h x microg/ml) at 1,500 and 2,000 mg/m, respectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels > or = 0.05 micromol/l was observed, with a predicted time of 10.4 h to decrease cell count by 50%. A correlation was also observed between percentage reduction of platelet count and gemcitabine Cmax, with a predicted effective concentration to induce a 50% decrease of 14.3 microg/ml.
This study demonstrates the lack of interaction between drugs, the nonproportional pharmacokinetics of gemcitabine at higher doses and the Emax relationship of paclitaxel and gemcitabine with neutrophil and platelet counts, respectively. In addition, gemcitabine 1,500 mg/m2 is the recommended dosage in combination with paclitaxel 100 mg/m2 for future phase II studies, due to its predictable kinetic behaviour and less severe thrombocytopenia than expected.
吉西他滨和紫杉醇是治疗非小细胞肺癌（NSCLC）最有效的两种药物，对包含这些药物的联合治疗方案进行药理学研究可能为优化治疗提供宝贵机会。本研究在一项I期研究中调查了初治晚期NSCLC患者中紫杉醇和吉西他滨的药代动力学和药效学。
患者静脉输注100mg/m²紫杉醇，输注1小时，随后分别以30分钟给药1500、1750和2000mg/m²吉西他滨。采用高效液相色谱法（HPLC）测定血浆中紫杉醇、吉西他滨及其代谢产物2',2'-二氟脱氧尿苷（dFdU）的水平。通过房室和非房室方法对浓度-时间曲线进行建模，并根据S型最大效应（Emax）模型拟合药代动力学/药效学（PK/PD）关系。
吉西他滨剂量从1500mg/m²增至2000mg/m²时，紫杉醇的药代动力学未发生改变。分别在1500mg/m²和2000mg/m²剂量下，观察到吉西他滨血浆峰浓度（Cmax，从18.56±4.94增至40.85±14.85μg/ml）和血浆浓度-时间曲线下面积（AUC，从9.99±2.75增至25.01±9.87h×μg/ml）呈非比例增加，提示高剂量时出现饱和动力学。观察到中性粒细胞减少与紫杉醇血浆浓度≥0.05μmol/l的时间之间存在显著关系，预测使细胞计数降低50%的时间为10.4小时。还观察到血小板计数降低百分比与吉西他滨Cmax之间存在相关性，预测诱导血小板计数降低50%的有效浓度为14.3μg/ml。
本研究证明了药物之间缺乏相互作用，高剂量时吉西他滨的非比例药代动力学，以及紫杉醇和吉西他滨分别与中性粒细胞和血小板计数之间的Emax关系。此外，鉴于其可预测的动力学行为以及血小板减少症比预期轻，吉西他滨150mg/m²是未来II期研究中与100mg/m²紫杉醇联合使用的推荐剂量。
