Peng B, English M W, Boddy A V, Price L, Wyllie R, Pearson A D, Tilby M J, Newell D R
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, U.K.
Eur J Cancer. 1997 Oct;33(11):1823-8. doi: 10.1016/s0959-8049(97)00341-9.
Cisplatin is an important drug in the treatment of a number of paediatric cancers yet, despite widespread use, there are only very limited data on the pharmacokinetics of the drug in children. Cisplatin pharmacokinetics were studied in 21 patients following a 24 h infusion of 50-120 mg/m2 cisplatin. Total and free platinum (Pt) levels in plasma and Pt in urine, were measured by atomic absorption spectrophotometry. Pharmacokinetic parameters were determined by non-compartmental and compartmental analyses. There was 3-fold interpatient variability in free drug exposure (area under the plasma concentration versus time curve--AUC) for a given surface area-based dose of cisplatin. The mean (+/- SD) pharmacokinetic parameters for free Pt were: AUC 0.47 +/- 0.13 mg/ml.min/100 mg/m2, Vdss 12.5 +/- 2.7 l/m2, t1/2 39 +/- 9 min, Ke 0.019 +/- 0.006 min-1, Clrenal 62 ml/min/m2, Cltotal 233 +/- 455 ml/min/m2, Cpss 0.31 +/- 0.09 microgram/ml. The total free Pt clearance was 1.5-5.8-fold higher (3.4 +/- 1.0) than the glomerular filtration rate (GFR). The renal clearance of cisplatin was not related to GFR and cisplatin was subject to only limited urinary excretion (27% administered dose 0-48 h), indicating that there are other important pathways of clearance beside renal elimination. Patient and treatment heterogeneity precluded the investigation of pharmacokinetic-pharmacodynamic relationships; however, the degree of interpatient pharmacokinetic variability observed suggests that body surface area-based dosing of cisplatin in children is not satisfactory.
顺铂是治疗多种儿童癌症的重要药物，然而，尽管其广泛应用，但关于该药物在儿童体内的药代动力学数据却非常有限。对21例接受50 - 120mg/m²顺铂24小时输注的患者进行了顺铂药代动力学研究。采用原子吸收分光光度法测定血浆中总铂和游离铂（Pt）水平以及尿中Pt水平。通过非房室分析和房室分析确定药代动力学参数。对于给定的基于体表面积的顺铂剂量，游离药物暴露量（血浆浓度-时间曲线下面积 - AUC）在患者间存在3倍的差异。游离铂的平均（±标准差）药代动力学参数为：AUC 0.47±0.13mg/ml·min/100mg/m²，稳态分布容积Vdss 12.5±2.7l/m²，半衰期t1/2 39±9分钟，消除速率常数Ke 0.019±0.006min⁻¹，肾清除率Clrenal 62ml/min/m²，总清除率Cltotal 233±455ml/min/m²，稳态血药浓度Cpss 0.31±0.09μg/ml。总游离铂清除率比肾小球滤过率（GFR）高1.5 - 5.8倍（3.4±1.0）。顺铂的肾清除率与GFR无关，且顺铂仅经有限的尿液排泄（0 - 48小时给药剂量的27%），这表明除肾脏消除外还存在其他重要的清除途径。患者和治疗的异质性妨碍了药代动力学-药效学关系的研究；然而，观察到的患者间药代动力学变异性程度表明，基于体表面积给儿童使用顺铂并不理想。
