Moore Andrew S, Norris Ross, Price Gareth, Nguyen Thu, Ni Ming, George Rani, van Breda Karin, Duley John, Charles Bruce, Pinkerton Ross
Queensland Children's Cancer Centre, Royal Children's and Mater Children's Hospitals, Australia.
J Paediatr Child Health. 2011 Dec;47(12):875-82. doi: 10.1111/j.1440-1754.2011.02103.x. Epub 2011 Jun 9.
Vincristine is a key component of many childhood cancer treatment regimens. Pharmacodynamic parameters such as clinical efficacy and toxicity may be influenced by polymorphisms of CYP3A.
The aim of this study was to document CYP3A5 genotype, vincristine pharmacokinetics (PK) and neurotoxicity profile for 50 children with cancer and determine whether, in a population of Australian children, the CYP3A5 genotype influenced the pharmacodynamics of vincristine as reflected by peripheral neurotoxicity.
Blood for PK analysis was collected after any single dose of vincristine and assayed using high performance liquid chromatography with tandem mass spectrometry detection. CYP3A53 and CYP3A56 genotype was determined using gel-electrophoresis or automated microfluidic electrophoresis. Neurotoxicity was determined by physical examination.
The median age of children sampled was 6.5 years (range 1-16.25). Half the patients received concurrent corticosteroids for acute lymphoblastic leukaemia. Six patients (12%) had experienced grade 3 or 4 neurotoxicity. The median clearance, area under the curve and Cmax of vincristine was 482 mL/min/m(2) (range 132-698), 49.7 mcg/L.h (16.5-143.1) and 3.5 mcg/L (1.0-31.2), respectively. In contrast to prediction, all but three children were homozygous for wild-type CYP3A53. No CYP3A56 polymorphisms were identified.
No correlation was identified between vincristine clearance, vincristine neurotoxicity, age, sex or concomitant steroid therapy. The limited sampling methodology proved acceptable to patients and families and would be suitable for larger scale studies including a wider range of genotypic variants and more detailed prospective evaluation of neurotoxicity.
长春新碱是许多儿童癌症治疗方案的关键组成部分。临床疗效和毒性等药效学参数可能受CYP3A基因多态性的影响。
本研究旨在记录50例癌症儿童的CYP3A5基因型、长春新碱药代动力学（PK）和神经毒性特征，并确定在澳大利亚儿童群体中，CYP3A5基因型是否会影响以周围神经毒性为反映的长春新碱药效学。
在任何单次长春新碱给药后采集用于PK分析的血液，并采用高效液相色谱-串联质谱检测法进行测定。使用凝胶电泳或自动微流控电泳确定CYP3A53和CYP3A56基因型。通过体格检查确定神经毒性。
采样儿童的中位年龄为6.5岁（范围1 - 16.25岁）。一半的患者因急性淋巴细胞白血病同时接受皮质类固醇治疗。6例患者（12%）出现3级或4级神经毒性。长春新碱的中位清除率、曲线下面积和Cmax分别为482 mL/min/m²（范围132 - 698）、49.7 mcg/L·h（16.5 - 143.1）和3.5 mcg/L（1.0 - 31.2）。与预测相反，除3名儿童外，所有儿童均为野生型CYP3A53纯合子。未鉴定出CYP3A56多态性。
未发现长春新碱清除率、长春新碱神经毒性、年龄、性别或同时进行的类固醇治疗之间存在相关性。有限采样方法被患者和家属所接受，适用于包括更广泛基因型变体和更详细神经毒性前瞻性评估的大规模研究。
