PHARMACOKINETICS OF VINCRISTINE IN CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOCYTIC-LEUKEMIA
PHARMACOKINETICS OF VINCRISTINE IN CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOCYTIC-LEUKEMIA
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DOI：
10.1016/s0022-3476(94)70027-3
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发表时间：
1994-10-01
影响因子：
5.1
通讯作者：
EVANS, WE
中科院分区：
文献类型：
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作者：
CROM, WR;DEGRAAF, SSN;EVANS, WE
我们通过特定的高效液相色谱分析、紫外和电化学检测以及有限取样策略，研究了长春新碱在急性淋巴细胞白血病儿童中的药代动力学。我们的目标是描述儿科患者中长春新碱的分布特征，确定与长春新碱药代动力学参数变异相关的临床、人口统计学或生化变量，并评估药代动力学参数与长春新碱神经毒性之间的关系。在3分钟内快速静脉注射后5和30分钟以及1、3和24小时收集血浆样本。通过图表审查回顾性评估长春新碱引起的神经毒性。对 54 名 2 个月至 18 岁（中位年龄 4.3 岁）儿童（包括 2 个月大的单卵双胞胎女孩）完成了 64 剂药代动力学研究。通过贝叶斯方法估计的长春新碱清除率变化很大，平均 (SD) 清除率为每公斤 19.9 (14.9) 毫升/分钟或每平方米 482 (342) 毫升/分钟。所有受试者的平均清除速度都快于已发表的成人研究，这可能部分与我们研究中使用的检测方法具有更高的特异性，以及与年龄相关的药物分布差异有关。长春新碱相关的神经毒性很常见，但较轻微，并且不能通过长春新碱全身暴露来预测；然而，神经毒性可能被低估了。一名接受戊巴比妥联合治疗的患者的清除率超过了所有患者的 75%，而接受联合组胺 (2) 拮抗剂的 5 名患者中有 4 名的清除率低于所有受试者的 25%，这表明诱导或抑制肝细胞色素 P-450 酶的药物可能会影响长春新碱的处置。需要进一步的研究来确定导致患者间长春新碱处置差异的因素，并制定改进的剂量指南。
We studied the pharmacokinetics of vincristine in children with acute lymphocytic leukemia by means of a specific high-performance liquid chromatographic assay with ultraviolet and electrochemical detection and a limited sampling strategy. Our objectives were to characterize the disposition of vincristine in pediatric patients, to determine clinical, demographic, or biochemical variables related to variability in vincristine pharmacokinetic parameters, and to assess the relationship between pharmacokinetic parameters and vincristine neurotoxicity. Plasma samples were collected at 5 and 30 minutes, and 1, 3, and 24 hours after a rapid intravenous injection during 3 minutes. Vincristine-induced neurotoxicity was retrospectively evaluated by chart review. Pharmacokinetic studies were completed for 64 doses in 54 children between 2 months and 18 years of age (median, 4.3 years), including 2-month-old monozygous twin girls. Vincristine clearance, estimated by Bayesian methods, was highly variable, with a mean (SD) clearance of 19.9 (14.9) ml/min per kilogram or 482 (342) ml/min per square meter. Mean clearance for all subjects was faster than In published studies of adults, which may be related in part to the greater specificity of the assay used in our study, as well as to age-related differences in drug disposition. Vincristine-associated neurotoxicity was frequent but mild and was not predicted by vincristine systemic exposure; however, neurotoxicity may have been underestimated. Clearance in one patient who received concomitant treatment with pentobarbital exceeded the 75th percentile for all patients, and four of five patients receiving concomitant histamine(2) antagonists had clearances below the 25th percentile for all subjects, suggesting that drugs that induce or inhibit hepatic cytochrome P-450 enzymes may affect vincristine disposition. Further studies are needed to identify the factors responsible for interpatient variability in vincristine disposition and to develop improved dosing guidelines.