预测胰岛素类似物的人类半衰期:一种跨药物方法
Kristian M Bendtsen1, Magnus W H Harder2, Tine Glendorf3
1Digital Sciences & Innovation, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark.
概括
使用胰岛素类别的药理动力学数据的药物间方法提供了比全米缩放更可靠的人类转化半衰期. 这种方法只需要来自一种动物物种的数据,从而提高了预测准确度.
科学领域:
- 药理动力学 药理动力学
- 药物开发 药物开发
- 翻译科学 翻译科学
背景情况:
- 从动物模型中预测人类的药理动力学对于药物开发至关重要.
- 全尺度缩放是一种常见的方法,但其对胰岛素类型的准确性可能是有限的.
- 胰岛素类似物,特别是脂肪酸延长形式,需要精确的药理动力学预测.
研究的目的:
- 评估一种药物间的药理动力学方法,用于预测胰岛素类型的人类半衰期.
- 为了比较药物间方法的预测性能与全米缩放.
- 确定成功应用药物间方法的要求.
主要方法:
- 利用来自各种胰岛素类型的老鼠,狗和猪模型的药理动力学数据.
- 应用了利用半衰期和清除机制信息的药物间方法.
- 将预测与多种类全米缩放和体外受体亲和度数据的结果进行了比较.
主要成果:
- 药物间的方法实现了较低的平均折叠误差 (AFE) 1.2-1.7,相比多种类的全米缩放 (AFE 1.9).
- 实验室人类胰岛素受体亲和度数据为人类半衰期预测提供了2.3-2.6的更高的AFE.
- 成功应用要求半衰期至少有两个数量级的跨度和共享清除机制.
结论:
- 药物间的药理动力学方法为预测胰岛素类似物在人体中半衰期提供了更准确,更有效的方法.
- 这种方法减少了对广泛多种类数据的需求,简化了药物开发.
- 这些发现支持使用药物间缩放来预测乙化和非乙化胰岛素类似物的药理动力学.
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