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This population analysis described the pharmacokinetics of bortezomib after twice-weekly, repeat-dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.3 mg/m twice-weekly, on days 1, 4, and 8 during specific blocks or cycles of both trials and on day 11 of block 1 of study AALL07P1, in combination with multiagent chemotherapy. Blood samples were obtained and the plasma was harvested on day 8 over 0-72 hours postdose to measure bortezomib concentrations by liquid chromatography-tandem mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling. Covariates were examined using forward addition (P < .01)/backward elimination (P < .001). Data were included from 104 patients (49%/51% acute lymphoblastic leukemia/acute myelogenous leukemia; 60%/40% aged 2-11 years/12-16 years). Bortezomib pharmacokinetics were described by a 3-compartment model with linear elimination. Body surface area adequately accounted for variability in clearance (exponent 0.97), supporting body surface area-based dosing. Stratified visual predictive check simulations verified that neither age group nor patient population represented sources of meaningful pharmacokinetic heterogeneity not accounted for by the final population pharmacokinetic model. Following administration of 1.3 mg/m intravenous bortezomib doses, body surface area-normalized clearance in pediatric patients was similar to that observed in adult patients, thereby indicating that this dose achieves similar systemic exposures in pediatric patients.

这项群体分析描述了硼替佐米在参与两项临床试验的儿科患者中每周两次重复静脉给药后的药代动力学情况

复发急性淋巴细胞白血病的2期AALL07P1（NCT00873093）试验以及初治急性髓性白血病的3期AAML1031（NCT01371981）试验。对药代动力学参数的变异性来源进行了表征和量化，以支持给药建议。患者在两项试验的特定疗程或周期的第1、4和8天以及研究AALL07P1第1疗程的第11天，每周两次静脉注射1.3mg/m²硼替佐米，联合多药化疗。在给药后第8天的0至72小时采集血样并收集血浆，通过液相色谱 - 串联质谱法测量硼替佐米浓度。通过非线性混合效应模型分析浓度 - 时间数据。使用向前加入法（P <.01）/向后剔除法（P <.001）检查协变量。纳入了104例患者的数据（49%/51%为急性淋巴细胞白血病/急性髓性白血病；60%/40%年龄为2至11岁/12至16岁）。硼替佐米的药代动力学由具有线性消除的三室模型描述。体表面积充分解释了清除率的变异性（指数为0.97），支持基于体表面积的给药。分层视觉预测检查模拟证实，年龄组和患者群体均未代表最终群体药代动力学模型未考虑的有意义的药代动力学异质性来源。静脉注射1.3mg/m²硼替佐米剂量后，儿科患者的体表面积标准化清除率与成年患者中观察到的相似，从而表明该剂量在儿科患者中实现了相似的全身暴露。