The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Children Oncology Group Operations and Data Center, Monrovia, CA, USA.
Cancer Chemother Pharmacol. 2021 Aug;88(2):359-365. doi: 10.1007/s00280-021-04295-1. Epub 2021 May 22.
Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.
放线菌素 D 和长春新碱是常用的儿童癌症治疗细胞毒性药物。本前瞻性研究评估了这些药物在儿童中的药代动力学变异性和毒性。采集了 158 例患者的血样。采用高效液相色谱-串联质谱法测定放线菌素 D 或长春新碱的浓度。采用非房室模型法估算药代动力学参数。前瞻性收集目标毒性。放线菌素 D 药代动力学（n=52 例患者）高度可变。浓度-时间曲线下面积（AUC）的中位数（变异系数，CV%）为 332ng/mL·h（110%）；清除率为 4.6 L/h/m（90%）；半衰期为 25 h（60%）。无患者符合骨髓抑制的定义标准。多变量分析中，人口统计学和药代动力学参数均不能预测急性肝毒性。长春新碱药代动力学（n=132 例患者）显示出显著的变异性。AUC 的中位数（CV%）为 78ng/mL·h（98%）；清除率为 17.2 L/h/m（67%）；半衰期为 14.6 h（73%）。多变量分析显示，对于给定的 BSA，年龄的增加会导致神经病变增加，而对于给定的年龄，BSA 的增加会导致神经病变减少。结论：两种药物的药代动力学均高度可变。对于放线菌素 D，人口统计学和药代动力学参数与目标毒性之间无相关性。对于长春新碱，年龄和 BSA 与神经病变的相关性受到儿童年龄和 BSA 之间的相关性以及婴儿神经病变的可确定性的影响。变异性可能归因于两种药物的剂量减少和剂量上限。需要对幼儿进行基于 BSA 的剂量研究，以减少暴露的变异性。
