集成动态体外系统和机械吸收建模:pralsetinib的案例研究
Michael J Dolton1, Christine Bowman2, Fang Ma2
1Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Journal of pharmaceutical sciences
|July 13, 2024
概括
将动态体外模型与PBPK建模集成,可以改善口服药物吸收的预测. 这项研究将Tiny-TIM和Simcyp结合起来,以评估pralsetinib,一种具有低溶解度的RET抑制剂,从而提高对其生物可用性的理解.
科学领域:
- 药理动力学和药物新陈代谢
- 在维特罗和在模拟模型.
- 胃肠道生理学 胃肠道生理学
背景情况:
- 预测人类口服药物吸收对于药物开发至关重要.
- 动态体外系统和基于生理学的药理动力学 (PBPK) 建模是有希望的,但通常是单独使用的.
- 普拉塞西尼布是一种RET抑制剂,表现出BCSII类属性 (溶解度低,透度高),这给吸收带来了挑战.
研究的目的:
- 将动态体外吸收系统与PBPK建模集成.
- 使用组合方法研究pralsetinib的口服吸收.
- 为了提高人类口服吸收低可溶性化合物的预测.
主要方法:
- 利用Tiny-TIM动态体外模型模拟人类胃肠道状况.
- 在禁食条件下进行了用pralsetinib200 mg和400 mg的Tiny-TIM实验.
- 采用Simcyp PBPK软件 (V21) 来进行机械吸收建模,并结合Tiny-TIM可溶性数据.
主要成果:
- 在Tiny-TIM.中,普拉塞提尼布的禁食生物可用性为63% (200毫克) 和53% (400毫克).
- 在胃pH值升高的情况下,在400毫克的剂量下,生物可访问性下降了16%.
- PBPK建模预测了不同剂量的类似吸收分数,与观察到的暴露保持一致.
结论:
- 将动态体外系统与PBPK建模集成为预测人类口服吸收提供了强大的方法.
- 这种综合策略对于挑战像普拉塞西尼布这样的低溶性化合物特别有价值.
- 这项研究表明,结合实验和计算方法用于药理动力学预测的实用性.
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