Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.
Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.
复制标题
DOI：
10.1111/cts.12420
复制
发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Bhattacharya I
中科院分区：
文献类型：
--
作者：
Singh P;Rong H;Gordi T;Bosley J;Bhattacharya I
抑制肌肉生长抑制素（GDF - 8）途径已成为肌肉萎缩疾病的重要治疗范例。在这项研究中，我们对抗肌肉生长抑制素单克隆抗体MYO‐029进行了翻译药代动力学/药效学（PK/PD）分析，使用小鼠、大鼠、猴子、人的PK数据、125I标记的MYO‐029小鼠组织分布数据、SCID小鼠肌肉重量增加和猴子肌肉周长变化。该分析显示，小鼠和猴子体内效力显著变化（72 nM vs 1.3 μM对股四头肌50%的影响）。估计MYO - 029在人体内的中央清除率（0.38 mL/h/kg）比典型IgG单克隆抗体高出两倍以上。在两周静脉注射剂量为10mg /kg的患者中，MYO‐029的峰值和低谷稳定暴露预计分别仅达到在猴子中所见最大效果的50%和10%。这些回顾性分析结果表明，本试验中MYO - 029暴露产生强大疗效的可能性很低。
Suppression of the myostatin (GDF‐8) pathway has emerged as an important therapeutic paradigm for muscle‐wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO‐029, an anti‐myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with 125I‐labeled MYO‐029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs. 1.3 μM for 50% effect on quadriceps). Estimated central clearance of MYO‐029 (0.38 mL/h/kg) in humans was greater than twofold higher than typical IgG mAbs. Peak and trough steady‐state exposures of MYO‐029 in patients at biweekly intravenous doses of 10 mg/kg MYO‐029 are predicted to achieve only 50% and 10% of the maximum effect seen in monkeys, respectively. These retrospective analyses results suggest that the MYO‐029 exposures in this trial had a low probability of producing robust efficacy.