Han Chunyan, Sun Tiancheng, Chirumamilla Siri Kalyan, Bois Frederic Y, Xu Mandy, Rostami-Hodjegan Amin
Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, Manchester M13 9PL, UK.
Pharmaron Inc., Beijing 100176, China.
Pharmaceutics. 2023 Aug 30;15(9):2237. doi: 10.3390/pharmaceutics15092237.
The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration-time profiles in the systemic circulation, as a surrogate to the site of action. However, similarity of profiles from two formulations in the systemic circulation does not imply similarity in the gastrointestinal tract (GIT) nor local BE. We have explored the concordance of BE conclusions for a set of hypothetical formulations based on budesonide concentration profiles in various segments of gut vs. those in systemic circulation using virtual trials powered by physiologically based pharmacokinetic (PBPK) models. The impact of Crohn's disease on the BE conclusions was explored by changing physiological and biological GIT attributes. Substantial 'discordance' between local and systemic outcomes of VBE was observed. Upper GIT segments were much more sensitive to formulation changes than systemic circulation, where the latter led to false conclusions for BE. The ileum and colon showed a lower frequency of discordance. In the case of Crohn's disease, a product-specific similarity factor might be needed for products such as Entocort EC to ensure local BE. Our results are specific to budesonide, but we demonstrate potential discordances between the local gut vs. systemic BE for the first time.
建立生物等效性（BE）最常用的方法是证明体循环中浓度-时间曲线的相似性，以此作为作用部位的替代指标。然而，两种制剂在体循环中的曲线相似性并不意味着在胃肠道（GIT）中的相似性，也不意味着局部生物等效性。我们利用基于生理的药代动力学（PBPK）模型进行虚拟试验，根据布地奈德在肠道各段与体循环中的浓度曲线，探讨了一组假设制剂的生物等效性结论的一致性。通过改变胃肠道的生理和生物学属性，研究了克罗恩病对生物等效性结论的影响。观察到虚拟生物等效性的局部和全身结果之间存在显著的“不一致”。上消化道段对制剂变化比体循环敏感得多，而体循环会导致生物等效性的错误结论。回肠和结肠的不一致频率较低。对于克罗恩病，像Entocort EC这样的产品可能需要特定产品的相似性因子来确保局部生物等效性。我们的结果特定于布地奈德，但我们首次证明了局部肠道与全身生物等效性之间存在潜在的不一致。
