生物制药分类系统的风险评估 第四类 含有即时释放产品的分子:使用体预测工具和基于生理学的药物动力学建模
Sivacharan Kollipara1, Mahendra Chougule2, Karthik Parsa3
1Biopharmaceutics Group, Global Clinical Management, Integrated Product Development Organization (IPDO), Dr. Reddy's Laboratories Ltd, Bachupally, Medchal Malkajgiri District, Hyderabad, 500 090, Telangana, India. sivacharankollipara@drreddys.com.
亚胺杂质 (NDSRI) 在药物中构成致癌风险. 基于生理学上的药理动力学 (PBPK) 建模为BCS IV分子提供了替代生物等价性方法,评估风险并确保药物安全.
科学领域:
- 药理动力学和药物新陈代谢
- 制药监管科学 制药监管科学
背景情况:
- 氨酸和与药物相关的杂质 (NDSRI) 是强大的致癌物质,需要严格的监管控制.
- 药物产品的偏差导致NDSRI检测后生物等价性研究需要额外的昂贵研究.
- 目前的USFDA指南为BCS I-III药物提供了体外替代品,但建议PBPK用于BCS IV即时释放 (IR) 配方.
研究的目的:
- 讨论生理学基础药理动力学 (PBPK) 建模的应用,作为BCS IV IR产品的替代生物等价性 (BE) 方法.
- 评估基于分子结构的NDSRI早期风险预测的内部in silico工具.
- 评估改变的透性和载体动力学对抗氧化剂在临床暴露的影响.
主要方法:
- 利用公司内部的in silico工具进行结构分析和预测37个BCS IV分子的致癌潜力.
- 使用PBPK建模对五种高风险BCS IV分子 (埃多克萨班,塞卢美替尼布,博苏替尼布,罗塞米德,化亚) 进行了临床暴露风险评估.
- 评估了透性变化 (±10-20%) 和传送器动力学对药物暴露的影响,以定义"透性安全空间".
主要成果:
- 成功预测了37个BCS IV分子的致癌潜力,并确定了5个用于进一步详细的风险评估.
- PBPK模型证明了改变的透性和传送器功能的影响药物暴露,特别是与抗氧化剂.
- 通过评估微小的透性变化对临床暴露的影响来确定"透性安全空间".
结论:
- PBPK建模为BCS IV IR产品提供了可行的替代生物等价性策略,减轻了与NDSRI相关的风险.
- 在 silico 工具和 PBPK 建模可以主动识别和管理 NDSRI 风险,从而避免昂贵的批准后研究.
- 通过PBPK建模来定义"透性安全空间",可以确保生物等价性,尽管配方变化会影响吸收.
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