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在药物发现中的基假设测试:使用定量系统药理学建模来评估对2型糖尿病糖尿病转化为胰岛素治疗的治疗价值
Maria E Trujillo1, Yue Han1, Rebecca A Baillie2
1Merck & Co., Inc., Rahway, NJ 07065, USA.
Pharmaceutics
|December 31, 2025
概括
在2型糖尿病中开发来将益胰岛素转化为胰岛素对HbA1c的影响很小. 这种定量系统药理 (QSP) 建模表明这种干预策略的治疗价值有限.
科学领域:
- 药理学 药理学是指药理学的学科.
- 计算生物学 计算生物学
- 内分泌学 在内分泌学.
背景情况:
- 胰岛素的前体益胰岛素具有较低的胰岛素受体活性.
- 增加的亲胰岛素水平与2型糖尿病的胰岛素抵抗相关,原因是β细胞处理受损.
- 量化系统药理 (QSP) 建模可以评估新的治疗策略.
研究的目的:
- 用QSP模型评估将循环中的益胰岛素转化为胰岛素的治疗潜力.
- 为了确定这样的干预是否可以改善2型糖尿病的葡萄糖平衡.
主要方法:
- 将亲胰岛素生物学集成到现有的葡萄糖恒温的QSP模型中.
- 开发和验证的虚拟患者 (VPs) 代表2型糖尿病亚群.
- 模拟临床试验,以评估益胰岛素转化为胰岛素对HbA1c的影响.
主要成果:
- 胰岛素转换在虚拟患者中产生了适度的~0.2%的HbA1c降低,被认为没有治疗意义.
- 对HbA1c的有限影响归因于益胰岛素的缓慢分泌和清除率,导致对血胰岛素的影响最小.
- 临床上显著的HbA1c降低需要超出生理范围的亲胰岛素/胰岛素比率.
结论:
- 用QSP建模进行in silico假设测试,有效地预测新型干预措施的成功概率.
- 这种方法提供了对治疗价值的洞察力,时间和资源减少.
- QSP建模可以指导药物发现决策,优化制药行业的资源配置.
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