个体内的药物动力学变异性对生物等价性研究中的个体暴露率有很大的影响,因此对药物配方的可互换性有很大影响
Philippe Lechat1,2, Fatma Kir3,4, Pierre Marquet5
1Paris-cité University, Paris, France. philippe.lechat@aphp.fr.
European journal of clinical pharmacology
|September 22, 2023
概括
通用药物的可互换性取决于个体药物暴露率. 在仿制药或参考药物中,个体内更高的差异增加了比率超出可接受的生物等效限的风险,特别是在狭窄治疗指数 (NTI) 药物中.
科学领域:
- 药理动力学和药物新陈代谢
- 制药科学 制药科学
- 生物统计学 生物统计学
背景情况:
- 生物等价性确保仿制药与参考药物具有相似的血液暴露,通常在±20% (或±10%的狭窄治疗指数 (NTI) 药物) 范围内.
- 个体药物暴露比率可以超过这些标准生物等效限值.
- 了解影响这些比率的因素对于评估药物互换性至关重要.
研究的目的:
- 分析影响仿制药和参考药物之间个体暴露比率的参数.
- 确定可靠的参考/仿制药互换性条件.
- 为了研究体内变异对药物暴露比率的影响.
主要方法:
- 对虚拟药物进行模拟生物等价性研究,使用双重交叉设计.
- 采用了100个随机集,在曲线下面积 (AUC) 的数量各不相同 (12,24,48,或100).
- 不同的通用/参考AUC几何平均比率 (0.80-1.25) 和个体内暴露差异.
主要成果:
- 在参考药物和仿制药中增加的患者内部变异,以及仿制药/参考药物平均AUC比率从1.0分歧,所有这些都提高了接受间隔之外的比率的患者比例.
- 仅对参考药物而言,人体内差异标准偏差≥0.25 (CV%>25%) 会导致个人暴露比率超过NTI药物的0.5-2范围.
- 较高的通用与参考内主体差异比率也增加了比率超出生物等效限的可能性.
结论:
- 药物可互换性,特别是NTI药物,要求仿制药在主体内的差异小于或等于参考药物的差异.
- 如果基因在人体内的差异超过参考值,则个体暴露比率的分布必须保持在参考药物的治疗边际内.
- 这些发现凸显了在确保安全有效的仿制药替代方面,个体内变化的关键作用.
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