Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers
Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers
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DOI：
10.1007/s40261-016-0437-4
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发表时间：
2016-11-01
影响因子：
3.2
通讯作者：
Feagan, Brian G.
中科院分区：
文献类型：
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作者：
Rosario, Maria;Wyant, Timothy;Feagan, Brian G.
Vedolizumab 是一种针对 α(4)β(7) 整合素的人源化单克隆抗体，适用于治疗中度至重度活动性溃疡性结肠炎或克罗恩病。在这项安慰剂对照、双盲、随机、单剂量递增研究中，在健康志愿者中评估了维多珠单抗的药代动力学、药效学、安全性和耐受性。 49 名参与者（分为 5 个队列）以 4:1 的比例随机分配，接受单次静脉输注维多珠单抗（0.2、0.5、2.0、6.0 或 10.0）毫克/千克）或安慰剂。收集血样用于测量维多珠单抗血清浓度和维多珠单抗对外周血淋巴细胞的α(4)β(7)饱和度。使用非房室方法计算药代动力学参数。监测不良事件。维多珠单抗观察到的最大血清浓度 (C (max)) 证明了测试剂量范围内的剂量比例。从 0.2 mg/kg 到 2.0 mg/kg，观察到血清浓度-时间曲线下面积从时间 0 到无穷大 (AUC(0-inf)) 的增加大于剂量比例，且末端消除半衰期 (t (1/2)) 更短，表明较低剂量下存在非线性药代动力学。当剂量高于 2.0 mg/kg 时，这些参数按比例增加剂量。当血清中可测量维多珠单抗时，在所有剂量和时间点，α(4)β(7)的饱和度处于或接近最大水平(> 90%)。 39 名接受维多珠单抗治疗的参与者中，共有 21 名 (54%) 的抗药物抗体 (ADA) 呈阳性，11 名 (28%) 的 ADA 持续呈阳性。总体而言，没有明显的不良事件信号，包括严重感染或恶性肿瘤。维多珠单抗表现出靶标介导的处置，其特征是低浓度下快速、可饱和的非线性消除过程和高浓度下较慢的线性消除过程。在所有剂量下均观察到几乎完全的α(4)β(7)饱和。健康志愿者对单次静脉输注维多珠单抗的耐受性良好。
Vedolizumab, a humanized monoclonal antibody against the alpha(4)beta(7) integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers.Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and alpha(4)beta(7) saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored.Vedolizumab maximum observed serum concentration (C (max)) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC(0-inf)) and shorter terminal elimination half-life (t (1/2)) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of alpha(4)beta(7) was at or near maximal levels (> 90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent.Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete alpha(4)beta(7) saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.