建立临床相关的溶解规范用于预药物生物等价性风险评估:将溶解/透系统与在阿比拉酸中基于生理学的生物制药建模集成
Fulin Bi1, Yan Lin2, Baohong Zhang3
1Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
概括
这项研究开发了阿比拉酸 (ABA) 前药的溶解规格,以减少生物等价性风险. 一个单相生物相关溶解方法成功预测了临床结果,确保了产品质量和患者安全.
科学领域:
- 药理动力学和药物新陈代谢
- 制药科学 制药科学
- 生物制药生物制药公司
背景情况:
- 阿比拉乙酸 (ABA) 是BCS第四类前药物,由于其依赖pH的溶解性,食物效应和可变水解,因此存在生物等价性 (BE) 挑战.
- 酶激活要求和复杂的吸收概况增加了这种化合物的BE故障的风险.
研究的目的:
- 建立对阿比拉酸 (ABA) 的临床相关溶解规格.
- 用生物相关溶解和生理基础生物制药建模 (PBBM) 来减轻与高可变性前药物相关的生物等价性 (BE) 风险.
主要方法:
- 评估了两种溶解方法:双相 (胃肠道转移模拟) 和单相 (生物相关介质) 在禁食和食条件下.
- 进行了临床BE研究,透性评估,并使用了整合水解,食物效应和第一通代谢的 PBBM.
- 确定了阿比拉作为主要的吸收驱动器,其明显透系数高于ABA.
主要成果:
- 临床BE研究表明,在禁食/养状态下,一种配方 (A) 的不符合,但另一种配方 (B) 的符合.
- 两阶段方法证明了超和,但很复杂;单阶段方法平衡了区分能力和可行性.
- PBBM准确地预测了临床药理动力学 (<20%的误差),并为BE定义了溶解"安全空间".
结论:
- 将生物相关溶解与机械建模相结合,可以有效地减轻复杂,高可变性前药物如ABA的BE风险.
- 单相生物相关溶解方法为仿制药开发提供了一个可扩展的,生理相关的战略.
- 这种方法支持开发具有食物依赖吸收的复杂配方,确保产品的一致性能和患者安全.
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