Bristol-Myers Squibb K.K., Tokyo, Japan.
Bristol-Myers Squibb, Tokyo, Japan.
J Clin Pharmacol. 2021 Jan;61(1):64-73. doi: 10.1002/jcph.1698. Epub 2020 Jul 12.
A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time-varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2-compartment model with parallel linear (nonspecific) and Michaelis-Menten elimination from the central compartment and target-mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target-mediated elimination rate (V ) were statistically significant but not considered clinically relevant (magnitude < 20%). Time-varying M protein on V was statistically significant, and the magnitude was >20%; however, clinical implications in the setting of combination therapy were not expected. Model-predicted steady-state elotuzumab exposure in cycle 12 were similar in Japanese and non-Japanese patients and in Japanese patients with 0 and ≥1 prior lines of therapy. Elotuzumab 20 mg/kg intravenously every 4 weeks beginning in cycle 19 produced time-averaged concentrations similar to elotuzumab 10 mg/kg intravenously every 2 weeks, although maximum and minimum concentrations after elotuzumab 20 mg/kg intravenous every-4-week dosing were slightly higher and lower, respectively. In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time-varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma.
建立了群体药代动力学模型，以评估日本人种、先前的治疗线（0 或≥1）、时变 M 蛋白和维持剂量方案（从第 19 周期开始，每 2 周静脉注射 10mg/kg 或每 4 周静脉注射 20mg/kg）对接受来那度胺/地塞米松联合埃罗妥珠单抗治疗的多发性骨髓瘤患者埃罗妥珠单抗药代动力学的影响。埃罗妥珠单抗药代动力学特征为 2 室模型，具有来自中央室的平行线性（非特异性）和米氏消除以及来自外周室的靶介导消除。亚洲人种对非特异性清除率（CL）和中央分布容积、先前的治疗线对 CL、以及最大靶介导消除率（V ）有统计学意义，但不认为具有临床相关性（幅度＜20%）。时变 M 蛋白对 V 有统计学意义，幅度＞20%；然而，在联合治疗的情况下，预计不会有临床意义。在第 12 周期中，模型预测的稳态埃罗妥珠单抗暴露在日本人和非日本人患者以及有 0 或≥1 先前治疗线的日本患者中相似。从第 19 周期开始，每 4 周静脉注射 20mg/kg 的埃罗妥珠单抗产生的时间平均浓度与每 2 周静脉注射 10mg/kg 的埃罗妥珠单抗相似，尽管每 4 周静脉注射 20mg/kg 埃罗妥珠单抗后的最大和最小浓度分别略高和略低。总之，目前的分析表明，日本人种、先前的治疗线、时变 M 蛋白以及第 19 周期埃罗妥珠单抗给药方案的改变对日本多发性骨髓瘤患者埃罗妥珠单抗的药代动力学和暴露没有临床意义的影响。
