Sediq Ahmad, Kubbinga Marlies, Langguth Peter, Dressman Jennifer
National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
J Pharm Sci. 2014 Jan;103(1):65-70. doi: 10.1002/jps.23769. Epub 2013 Nov 8.
The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose-solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the "dose" in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate.
生物药剂学分类系统（BCS）根据活性药物成分的剂量-溶解度比来定义其溶解度特征：对于高溶解度药物，在规定的pH范围内，该比例小于250 mL。在2010年欧洲药品管理局（EMA，前身为EMEA）指南修订之前，该比例中的“剂量”在美国食品药品监督管理局（US FDA）、EMA和世界卫生组织（WHO）的生物豁免指南中一直被定义为最高剂量强度。然而，在修订后的EMA指南中，剂量被定义为根据产品特性摘要所施用的最高单次剂量。EMA关于高溶解度的新标准可能更接近实际使用情况，但它与体内生物等效性研究中使用的剂量不一致。本文评估了已发表的生物豁免专论中活性药物成分对BCS分类的影响，并讨论了分类可能变化对生物豁免建议的后果。根据EMA目前对剂量的定义，按照EMA标准，盐酸甲氧氯普胺和盐酸维拉帕米的生物豁免建议不再有效。对于泼尼松龙和泼尼松，考虑到通常的给药水平，重新评估生物豁免建议似乎是合适的。
