目的:了解进行早期生物等效性(BE)风险评估的参数的预测潜力对于产品开发期间的良好计划和风险缓解至关重要。本研究的目的是评估各种生物药物和药代动力学参数对BE研究结果的预测潜力。
方法:对198Sandoz(LekPharmaceuticalsd.d.,山德士公司,Verovskova57,1526卢布尔雅那,斯洛文尼亚)赞助的BE研究[52种活性药物成分(API)],其中收集了即时释放产品的BE研究和API的特征,并使用单变量统计分析评估了其对研究结果的预测潜力。
结果:生物制药分类系统(BCS)被证实对BE的成功具有很高的预测价值。使用难溶性API的BE研究(23%非BE)比使用高可溶性API(0.1%非BE)风险更大。具有较低生物利用度(BA)的API,存在首过代谢,和/或作为P-糖蛋白底物(P-gP)的底物与较高的非BE发生率有关。计算机通透性和峰值血浆浓度时间(Tmax)显示为预测BE结果的潜在相关特征。此外,我们的分析表明,对于具有多隔室模型描述的处置的难溶性API,非BE结果的发生率明显更高。在空腹BE研究的子集上,溶解性差的API的结论是相同的;对于喂食研究的子集,BE和非BE组的因素之间没有显着差异。
结论:了解参数与BE结果的关联对于进一步开发早期BE风险评估工具非常重要,在早期BE风险评估工具中,应首先关注寻找其他参数以区分一组难溶性API中的BE风险。
OBJECTIVE: Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present
study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE
study.
METHODS: Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE
study and APIs were collected for immediate-release products and their predictive potential on the
study outcome was assessed using univariate statistical analysis.
RESULTS: Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (Tmax) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. The conclusions for poorly soluble APIs were the same on a subset of fasting BE studies; for a subset of fed studies there were no significant differences between factors in BE and non-BE groups.
CONCLUSIONS: Understanding the association of parameters and BE outcome is important for further development of early BE risk assessment tools where focus should be first in finding additional parameters to differentiate BE risk within a group of poorly soluble APIs.