预测生物等价性和发展溶解生物等价性安全空间 in vitro 用生理学基础的药物动力学吸收模型用于华法林
Zi-Zhao Cheng1, Xiao Hu1, Ya-Li Li1
1Department of Pharmacology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nerve System Drugs,Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
概括
基于生理学的药理动力学 (PBPK) 模型可以预测像华法林这样的狭窄治疗指数 (NTI) 药物的生物等价性 (BE). 这项研究成功开发了华法林的PBPK模型,帮助开发仿制药和临床试验.
科学领域:
- 药理动力学和药物开发
- 在药理学中的计算建模.
- 生物等价性研究 生物等价性研究
背景情况:
- 生物等价性 (BE) 研究对于药物批准至关重要,但狭窄治疗指数 (NTI) 药物由于高成本和低临床试验成功率而面临挑战.
- 基于生理学的药理动力学 (PBPK) 建模为评估药物制剂的 BE 提供了一个潜在的解决方案,特别是在高风险的 NTI 药物中.
研究的目的:
- 开发和验证一种基于生理学的药理动力学 (PBPK) 模型,用于评估华法林2.5毫克片在中国人中的生物等价性 (BE).
- 建立与体内生物等价性相关的禁食条件下华法林的体外溶解极限.
- 证明PBPK建模在降低NTI药物的BE失败风险方面的实用性.
主要方法:
- 使用了 GastroPlusTM 软件,该软件包含了高级分区吸收和传输 (ACATTM) 模型.
- 华法林的输入物理和化学特性.
- 开发了PBPK模型,使用来自中国人禁食条件下的参考制剂的药理动力学数据.
- 用来自不同国内制造商的参考和测试制剂的数据验证了模型.
主要成果:
- 已确定的溶解极限:在pH 4.5下30分钟释放≥30%,在pH 6.8下30分钟释放≥80%.
- 证明在空腹条件下实现生物等价性可以显著降低在食华法林条件下发生BE失效的风险.
- 在中国人群中成功开发和验证了2.5毫克华法林片的PBPK模型.
结论:
- 基于生理学的药理动力学 (PBPK) 模型有效地开发了华法林2.5毫克片在中国人身上.
- 在专用软件中使用体外溶解数据开发PBPK模型是对狭窄治疗指数 (NTI) 药物的生物等价性评估的一个有希望和有价值的方法.
- 这种方法可以在开发新药和临床试验研究中对仿制药的生物等价性有显著的帮助.
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