Balis Frank M, Thompson Patrick A, Mosse Yael P, Blaney Susan M, Minard Charles G, Weigel Brenda J, Fox Elizabeth
The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, CTRB-4024, Philadelphia, PA, 19104, USA.
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27599, USA.
Cancer Chemother Pharmacol. 2017 Jan;79(1):181-187. doi: 10.1007/s00280-016-3220-6. Epub 2016 Dec 28.
Characterize the pharmacokinetics of oral crizotinib in children with cancer.
Sixty-four children with solid tumors or anaplastic large-cell lymphoma (ALCL) enrolled on a phase 1/2 trial of the ALK, MET and ROS1 inhibitor, crizotinib, had pharmacokinetic sampling after the first dose (n = 15) or at steady state (n = 49). Dose levels studied were 100, 130, 165, 215, 280 and 365 mg/m/dose administered twice daily. Two capsule and two oral liquid formulations were used over the course of the trial. Crizotinib was quantified with a validated HPLC/tandem mass spectrometry method with a lower limit of detection of 0.2 ng/mL. Pharmacokinetic parameters were derived using non-compartmental analysis.
Time to peak plasma concentration was 4 h. At 280 mg/m (MTD), mean (±SD) steady-state peak plasma concentration was 717 ± 201 ng/mL, and steady-state trough plasma concentration was 480 ± 176 ng/mL. At steady state, AUC was proportional to dose over the dose range of 215-365 mg/m/dose. Apparent clearance of crizotinib was 731 ± 241 mL/min/m. Steady-state AUC at 280 mg/m/dose was 2.5-fold higher than the AUC in adults receiving 250 mg (~140 mg/m). Age, sex and drug formulation do not account for the inter-subject variability in AUC at steady state. The accumulation index was 4.9, and the half-life estimated from the accumulation index was 36 h.
The pharmacokinetics of oral crizotinib in children is similar to that in adults. Steady-state trough-free crizotinib concentrations in plasma at the MTD exceed inhibitory concentrations of crizotinib in ALCL cell lines. CLINICALTRIALS.
NCT00939770.
描述克唑替尼口服制剂在患癌儿童中的药代动力学特征。
64名患有实体瘤或间变性大细胞淋巴瘤（ALCL）的儿童参与了ALK、MET和ROS1抑制剂克唑替尼的1/2期试验，在首剂用药后（n = 15）或稳态时（n = 49）进行了药代动力学采样。研究的剂量水平为每日两次给药，剂量分别为100、130、165、215、280和365mg/m/剂量。在试验过程中使用了两种胶囊和两种口服液体制剂。采用经过验证的HPLC/串联质谱法对克唑替尼进行定量，检测下限为0.2ng/mL。使用非房室分析得出药代动力学参数。
血浆峰浓度达峰时间为4小时。在280mg/m（最大耐受剂量）时，平均（±标准差）稳态血浆峰浓度为717±201ng/mL，稳态谷浓度为480±176ng/mL。在稳态时，在215 - 365mg/m/剂量的剂量范围内，AUC与剂量成正比。克唑替尼的表观清除率为731±241mL/min/m。280mg/m/剂量时的稳态AUC比接受250mg（~140mg/m）的成人高2.5倍。年龄、性别和药物制剂不能解释稳态时AUC的个体间差异。蓄积指数为4.9，根据蓄积指数估算的半衰期为36小时。
克唑替尼口服制剂在儿童中的药代动力学与成人相似。最大耐受剂量时血浆中克唑替尼的稳态谷浓度超过了克唑替尼在ALCL细胞系中的抑制浓度。临床试验。
NCT00939770。
