基于模型的跨物种缩放用于预测CB 4332的人类药理动力学,这是一个补充因子I蛋白
Rami Ayoun Alsoud1, Natacha Le Moan2, Lars Holten-Andersen2
1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Journal of pharmaceutical sciences
|June 30, 2024
概括
CB 4332的药理动力学建模为人类剂量选择提供了信息. 模型模拟建议每周用5毫克/公斤的皮下剂量达到疗效目标,考虑物种特异性清除和抗药抗体.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物技术是生物技术.
- 药物开发 药物开发
背景情况:
- CB 4332是一种150kDa重组补充因子I蛋白.
- 临床前药理动力学 (PK) 研究在小鼠,大鼠和非人类灵长类动物 (NHPs) 中进行.
- 了解跨物种PK对于选择首次给人剂量至关重要.
研究的目的:
- 为了进行CB 4332药理动力学的跨物种缩放.
- 根据CB 4332.的适当首次人体剂量的选择,提供信息.
- 为了比较传统和基于模型的 PK 方法.
主要方法:
- 同时建模从临床前研究中的PK数据,使用全米缩放.
- 纳入特定物种的清除参数,包括特定于老鼠的清除.
- 对抗药物抗体 (ADA) 诱导清除的估计,考虑到发病时间.
- 使用没有观察到不良反应水平 (NOAEL) 和剂量按因素方法计算人体等效剂量.
主要成果:
- 确定和建模了CB 4332消除的特定物种差异.
- 在老鼠和一些NHP中观察到抗药抗体 (ADA) 的形成,影响清除.
- 传统的剂量因子方法建议每周开始皮下 (SC) 剂量为0.9mg/kg.
- 模型模拟表明,预计每周使用 5 mg/kg 的 SC 剂量可以达到目标人体疗效度.
结论:
- 与传统方法相比,基于模型的PK分析提供了更精细的剂量选择方法.
- 考虑ADA形成对于准确的PK建模和剂量预测至关重要.
- 根据PK建模,预计每周5mg/kg的SC剂量CB 4332在人类中有效.
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