Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892-1101, USA.
Cancer Chemother Pharmacol. 2010 Sep;66(4):737-43. doi: 10.1007/s00280-009-1218-z. Epub 2010 Jan 1.
To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes.
Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75-250 mg/m(2)/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed.
ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t (1/2) of 5.1 h. The apparent clearance was 33 ml/min/m(2) and was age-independent. The AUC(0-infinity) increased in proportion to the dose, and at 200 mg/m(2) the median AUC(0-infinity) was 91 mcg h/ml and the C (ave) was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3-5 h after the dose. The glucuronide:sulfate molar AUC(0-infinity) ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC(0-infinity) was higher in patients experiencing dose-limiting toxicity.
Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.
描述神经母细胞瘤和其他实体瘤患儿口服 ABT-751 及其共轭代谢物的药代动力学，并将药代动力学参数与毒性和治疗结果相关联。
37 例神经母细胞瘤患者（中位年龄 11 岁）和 25 例其他实体瘤患者在接受 ABT-751（75-250mg/m2/天）单药治疗第 1 天进行药代动力学采样，用药方案为 7 天或 21 天。采用 HPLC/MS/MS 法检测 ABT-751 及其葡萄糖醛酸和硫酸盐代谢物。采用非房室模型法推导药代动力学参数。评估更水溶性胶囊和混悬剂配方的相对生物利用度。
ABT-751 于 2 小时在血浆中达峰，呈单指数衰减，t1/2 为 5.1 小时。表观清除率为 33ml/min/m2，与年龄无关。AUC（0-无穷大）与剂量成比例增加，200mg/m2 时的中位数 AUC（0-无穷大）为 91mcg h/ml，Cave 为 3.9mcg/ml。个体内和个体间的变异性较低。代谢物在给药后 30 分钟在血浆中被检测到，并在给药后 3-5 小时达到峰值。葡萄糖醛酸：硫酸盐摩尔 AUC（0-无穷大）比值为 0.57。少于 1%的剂量以原形药物从尿液中排泄；13%的剂量以硫酸盐代谢物排泄，10%以葡萄糖醛酸代谢物排泄。水溶性胶囊和混悬剂配方的相对生物利用度分别为 105%和 93%。发生剂量限制毒性的患者 AUC（0-无穷大）较高。
儿童口服 ABT-751 的药代动力学呈剂量比例且与年龄无关，个体内和个体间的变异性较小。
