Kisor D F, Plunkett W, Kurtzberg J, Mitchell B, Hodge J P, Ernst T, Keating M J, Gandhi V
Ohio Northern University, Ada, OH, USA.
J Clin Oncol. 2000 Mar;18(5):995-1003. doi: 10.1200/JCO.2000.18.5.995.
To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death.
The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations.
There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C(max)) of ara-G occurred at or near the end of the nelarabine infusion. The C(max) of ara-G ranged from 11.6 micromol/L to 308.7 micromol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C(max), time of the C(max), and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0. 213 L.h(-1).kg(-1)) (P <.001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P <.01).
Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.
描述奈拉滨（506U78）及其代谢产物9-β-D-阿拉伯呋喃糖鸟嘌呤（ara-G）在难治性血液系统恶性肿瘤儿童和成人患者中的药代动力学特征。ara-G在白血病细胞内磷酸化形成三磷酸ara-G（ara-GTP），从而终止DNA链延长，导致细胞死亡。
在治疗的第一天，对71例患者（25例儿童患者和46例成人患者）的奈拉滨和/或ara-G的药代动力学进行评估。在特定时间采集血液，以测定血浆中奈拉滨和ara-G的浓度。
各患者组之间奈拉滨的药代动力学无统计学显著差异。儿童患者和成人患者中奈拉滨的调和平均半衰期（t1/2）分别为14.1分钟和16.5分钟。ara-G的最大浓度（C(max)）出现在奈拉滨输注结束时或接近结束时。在奈拉滨剂量为5至75mg/kg时，ara-G的C(max)范围为11.6μmol/L至308.7μmol/L，且与奈拉滨剂量呈线性相关。成年男性和女性患者之间ara-G的药代动力学参数估计值无统计学显著差异。与成人相比，儿童的剂量标准化C(max)、C(max)出现时间以及ara-G的稳态分布容积相似。然而，儿童患者中ara-G的清除率（0.312L·h-1·kg-1）高于成人患者（0.213L·h-1·kg-1）（P<.001）。儿童患者中ara-G的t1/2短于成人患者（2.1小时对3.0小时；P<.01）。
奈拉滨是ara-G的有效前体药物，可使ara-G达到具有临床活性的全身浓度。
