de Graaf S S, Bloemhof H, Vendrig D E, Uges D R
Groningen Institute for Drug Studies (GIDS), Beatrix Children's Hospital, Division of Pediatric Hematology-Oncology, The Netherlands.
Med Pediatr Oncol. 1995 Apr;24(4):235-40. doi: 10.1002/mpo.2950240405.
Vincristine (VCR) has been widely used to treat childhood malignancies for over thirty years, but its plasma disposition has not yet been well-defined. Therefore, we conducted a pharmacokinetic study of VCR in 17 children with acute lymphoblastic leukemia (ALL) receiving the first dose of VCR. A new high-performance liquid chromatographic assay was used for the measurement of VCR in plasma. A two-compartment pharmacokinetic model was fit to the data by nonlinear least-squares regression. Estimated pharmacokinetic parameters were highly variable; mean (S.D.) volume of distribution at steady-state was 360 (176) L.m-2; total body clearance was 431 (238) ml.min-1.m-2, and elimination half-life was 823 (390) min. These results were compared to data from eight adults with lung cancer. Mean volume of distribution in adults and children were similar, but VCR clearance was significantly larger in children (P = 0.01), resulting in a significantly longer elimination half-life in the adults (P < 0.01). We conclude that administration of a standard dosage of VCR to children with ALL results in a highly variable systemic drug exposure, which may have implications for the oncolytic effect and/or toxicity in individual patients. Comparison of data from children and adults suggests that VCR elimination rate is a function of age; this could account for more severe neurotoxicity in older patients. However, it cannot be excluded that differences between the children and adults may be due to other variables than age. Future studies should focus on the possible influence of multidrug resistance modulating agents on VCR pharmacokinetics and on pharmacokinetic-pharmacodynamic relationships in individual patients.
三十多年来，长春新碱（VCR）一直被广泛用于治疗儿童恶性肿瘤，但其血浆处置情况尚未得到很好的界定。因此，我们对17例接受首剂VCR治疗的急性淋巴细胞白血病（ALL）患儿进行了VCR的药代动力学研究。采用一种新的高效液相色谱法测定血浆中的VCR。通过非线性最小二乘法回归将二室药代动力学模型拟合到数据中。估计的药代动力学参数高度可变；稳态时平均（标准差）分布容积为360（176）L·m⁻²；全身清除率为431（238）ml·min⁻¹·m⁻²，消除半衰期为823（390）分钟。将这些结果与8例肺癌成人患者的数据进行了比较。成人和儿童的平均分布容积相似，但儿童的VCR清除率明显更高（P = 0.01），导致成人的消除半衰期明显更长（P < 0.01）。我们得出结论，给ALL患儿使用标准剂量的VCR会导致全身药物暴露高度可变，这可能对个体患者的溶瘤效果和/或毒性产生影响。儿童和成人数据的比较表明，VCR消除率是年龄的函数；这可以解释老年患者更严重的神经毒性。然而，不能排除儿童和成人之间的差异可能是由于年龄以外的其他变量所致。未来的研究应关注多药耐药调节剂对VCR药代动力学以及个体患者药代动力学 - 药效学关系的可能影响。
