Northern Institute for Cancer Research, Medical School, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Cancer Chemother Pharmacol. 2010 May;65(6):1057-66. doi: 10.1007/s00280-009-1111-9. Epub 2009 Aug 23.
Carboplatin and etoposide are commonly used chemotherapeutics for the treatment of many paediatric cancers. However, there are very limited published data concerning the pharmacokinetics of these agents in infants and very young children, for whom dose reductions are frequently implemented.
Etoposide (5 mg/kg; 2 h i.v. infusion) was co-administered with carboplatin (6.6 mg/kg; 1 h i.v. infusion) on each of 3 days of treatment and samples were taken between 0.5 and 4 h after the start of administration, from a total of 19 neuroblastoma patients aged <1 year at diagnosis and weighing <12 kg at treatment. Pharmacokinetic analysis was carried out using a non-linear mixed effects modelling approach.
Two compartment structural models were selected for both carboplatin and etoposide analysis. Body weight (BW) was strongly associated with carboplatin clearance (Cl), with a slightly weaker relationship observed with etoposide Cl. Carboplatin Cl values ranged from 12.8 to 33.6 ml/min, with total AUC values of 4.2-9.3 mg/ml.min achieved over the 3 days of treatment. Cl values normalized to BW were significantly higher in patients <12 kg than in children >12 kg, with mean +/- SD values of 2.9 +/- 0.4 and 2.5 +/- 0.4 ml/min/kg, respectively (P < 0.05). Etoposide exhibited a median half-life of 4.6 h (range 4.1-6.6), a median AUC of 7.1 mg/ml.min (range 3.4-11.0) and a median Cl of 6.6 ml/min (range 3.2-13.0).
Results suggest that prediction of absolute carboplatin Cl values may be difficult in infant patients <12 kg, with a small but significant difference in Cl values normalized to BW observed in this patient group. Etoposide pharmacokinetic data support previous findings that question the utility of modified dosing in infants. The current study demonstrates the feasibility of generating informative pharmacokinetic data in infants and young children.
卡铂和依托泊苷是治疗多种儿科癌症的常用化疗药物。然而，对于婴儿和非常年幼的儿童，这些药物的药代动力学数据非常有限，因为他们经常需要减少剂量。
在 3 天的治疗中，每 2 小时静脉输注 5 毫克/千克依托泊苷（2 小时静脉输注），并在给药开始后 0.5 至 4 小时之间采集样本，共采集了 19 名诊断时年龄<1 岁且体重<12 公斤的神经母细胞瘤患者的样本。采用非线性混合效应模型分析进行药代动力学分析。
选择了卡铂和依托泊苷分析的两室结构模型。体重（BW）与卡铂清除率（Cl）密切相关，与依托泊苷 Cl 也有较弱的关系。卡铂 Cl 值范围为 12.8 至 33.6 毫升/分钟，3 天治疗期间总 AUC 值为 4.2-9.3 毫克/毫升/分钟。体重归一化的 Cl 值在<12 公斤的患者中明显高于>12 公斤的儿童，分别为 2.9 +/- 0.4 和 2.5 +/- 0.4 毫升/分钟/公斤（P < 0.05）。依托泊苷的中位半衰期为 4.6 小时（范围 4.1-6.6），中位 AUC 为 7.1 毫克/毫升/分钟（范围 3.4-11.0），中位 Cl 为 6.6 毫升/分钟（范围 3.2-13.0）。
结果表明，在体重<12 公斤的婴儿患者中，预测卡铂绝对 Cl 值可能很困难，在该患者组中观察到体重归一化的 Cl 值存在微小但显著的差异。依托泊苷药代动力学数据支持了之前质疑在婴儿中使用改良剂量的有效性的发现。本研究证明了在婴儿和幼儿中生成有意义的药代动力学数据的可行性。
