Sonnichsen D S, Hurwitz C A, Pratt C B, Shuster J J, Relling M V
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN.
J Clin Oncol. 1994 Mar;12(3):532-8. doi: 10.1200/JCO.1994.12.3.532.
Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics.
We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data.
Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (< 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (> 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage.
We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.
我们的目的是评估紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）在儿童中的药代动力学和药效学，并确定紫杉醇是否表现出饱和药代动力学。
在一项针对30例患有难治性实体瘤的儿科患者（年龄2.3至22.8岁）的1期研究中，我们评估了以24小时静脉输注方式给予的紫杉醇（200至420mg/m²）的药代动力学和药效学。在输注期间及输注后长达48小时内采集14份连续血样，并用高效液相色谱 - 紫外（HPLC - UV）法测定紫杉醇浓度。比较了四种药代动力学模型描述患者数据的能力。
紫杉醇的处置情况与一级二室药代动力学模型不一致。相反，大多数数据集最好用包含饱和组织分布和饱和消除的二室模型来描述；少数患者数据集最好用包含饱和分布或饱和消除的模型来描述。清除率呈剂量依赖性，较低剂量（<400mg/m²）时的中位清除率为161mL/min/m²，最高剂量（>400mg/m²）时为123mL/min/m²（P = 0.044）。紫杉醇血浆浓度超过0.1μmol/L的持续时间差异很大（范围为26至71小时）。与无毒性的儿童相比，患有肌肉骨骼毒性（72μmol/L·h；P = 0.054）或神经毒性（54μmol/L·h；P = 0.062）的儿童的浓度 - 时间曲线下面积（AUC）中位数有升高趋势。毒性与剂量无显著相关性。
我们得出结论，紫杉醇的分布和消除是饱和的，并且紫杉醇全身暴露的估计值与毒性的相关性比与剂量的相关性更好。
