修改释放口服配方与非线性肠道吸收的生理学基础上的 in vitro - in vivo 相对关系:使用mirabegron的案例研究
Yoshinori Takahashi1, Atsushi Kambayashi1
1Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
概括
开发一种基于生理学的生物制药模型 (PBBM),改善了mirabegron修改释放 (MR) 配方的体外-体内相关性 (IVIVC). 这种方法准确地预测了Cmax,但由于结肠吸收建模,AUC预测存在局限性.
科学领域:
- 药物动力学和生物制药学
- 药物输送系统 药物输送系统
背景情况:
- 为了取代生物等价性 (BE) 研究,确定修改释放 (MR) 配方的体外-体内相关性 (IVIVC) 是至关重要的,但目前的方法往往由于对生理吸收机制的考虑不足而失败,特别是对于具有非线性吸收的药物.
- 用于过度活跃的膀的米拉贝格朗表现出非线性吸收,这对传统的IVIVC发展构成了挑战.
研究的目的:
- 开发一种基于生理学的生物制药模型 (PBBM),能够实现Mirabegron MR配方的A级IVIVC.
- 针对具有非线性吸收特征的药物建立IVIVC的常规方法的局限性.
主要方法:
- 根据立即释放配方的人类药理动力学 (PK) 数据计算了mirabegron的光线药物度依赖的膜透系数.
- 将导出的透系数应用于MR配方的PK数据,以估计体内溶解速率,假设是零级速率方程.
- 使用估计的体内溶解率和文献报告的体内溶解率生成Levy图表,并利用PBBM预测mirabegron MR配方的口服PK.
主要成果:
- 以生理学为基础的体外-体内相关性 (PB-IVIVC) 方法成功地产生了线性Levy图形,在不同剂量和溶解配置中,mirabegron MR配方的斜率接近1.0.
- MR配方的峰值血度 (Cmax) 值被PBBM准确地预测.
- 曲线下面积 (AUC) 的预测错误超过了A级IVIVC标准,这表明模型对结肠吸收的描述存在潜在问题.
结论:
- 开发的 PBBM 提供了一个有前途的方法,用于建立 mirabegron MR 配方的 A 级 IVIVC,特别是预测 Cmax.
- 进一步完善PBBM以更好地纳入结肠吸收机制是必要的,以提高AUC预测的准确性,并满足A级IVIVC标准.
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