Garetosmab的药代学和药效学(Anti-Activin):结果First-in-Human第一阶段研究。

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梁Vanhoutte F,年代,红米,赵,首席伊朗研究员Drewery T,王Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M,赫尔曼·G,戴维斯JD

Garetosmab的药代学和药效学(Anti-Activin):结果First-in-Human第一阶段研究。

中国新药杂志。2020年11月,60 (11):1424 - 1431。doi: 10.1002 / jcph.1638。Epub 2020年6月18日。

PubMed ID

32557665 (在PubMed

]

文摘

我们描述garetosmab first-in-human研究的结果(一个完全人类单克隆抗体,抑制苯丙酸诺龙)正在开发的治疗fibrodysplasia ossificans progressiva (FOP)。双盲,安慰剂对照第一阶段的研究中,40名健康女性nonchildbearing潜在的被随机分配接受单剂量静脉garetosmab 0.3, 1, 3,或10毫克/公斤;皮下garetosmab 300毫克;或安慰剂。血清浓度的功能性garetosmab(> / = 1手臂自由绑定到目标),总苯丙酸诺龙、反麻醉品的抗体测定初始剂量和113天邮报》率先剂量。Garetosmab演示了一个可以接受的安全性没有dose-limiting毒性。Garetosmab显示非线性与target-mediated消除药物动力学。随着剂量的静脉garetosmab,意味着dose-proportional方式峰值浓度增加;意思是稳态估计范围从41.4到47.8毫升/公斤。大于dose-proportional增加意味着曲线下的面积从时间零外推到无穷(72.2,-7520毫克*天/ L)观察,符合减少意味着间隙(范围4.35 - -1.34毫升/天/公斤)。 Following administration of intravenous garetosmab, mean concentrations of total activin A increased in a dose-dependent manner. At 10 mg/kg, total activin A levels reached a state of little or no change between weeks 4 and 12, suggesting saturation of the target-mediated pathway. No safety signals were seen in this study to preclude investigation in patients. Following intravenous administration, garetosmab concentrations decreased quickly, then decreased over time (reflecting linear elimination), and finally decreased in a nonlinear phase, reflecting target-mediated elimination. Results here support further investigation. Garetosmab 10 mg/kg every 4 weeks intravenously is being evaluated in patients with FOP (NCT03188666).

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药物

Garetosmab