Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Brazil.
Drug Dev Ind Pharm. 2021 Dec;47(12):1881-1894. doi: 10.1080/03639045.2022.2062377. Epub 2022 Apr 11.
Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) have been clinically used in the treatment of coagulation disorders. There are four DOACs approved since 2010 (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban), and they were designed to overcome the practical limitations of VKA. This review summarized biopharmaceutics considerations about DOACs, which are critically discussed, applying risk analyses to subside the further classification of these drugs according to the Biopharmaceutics Classification System (BCS). These discussions included data compiled about physicochemical properties, equilibrium solubility, permeability, and drug dissolution of DOACs. From the biopharmaceutics characteristics is possible to identify critical variables related to the absorption process, which can help in the design of new formulations. The data were compared with the criteria recommended by regulatory agencies for the biopharmaceutics classification according to the BCS. From that, these data may be used to discuss the approval of generic medicines by the BCS-based biowaiver, and the clinical risks arising from novel formulations with DOACs. However, although there are indications of biopharmaceutics classifications for DOACs, conclusive information to classify these compounds according to the BCS is lacking, requiring more experimental studies to achieve this aim. Conclusive information is essential for a safe decision about the biowaiver, as well as to guide the development of new formulations containing the DOACs.
维生素 K 拮抗剂（VKA）和直接口服抗凝剂（DOAC）已在凝血障碍的治疗中得到临床应用。自 2010 年以来，已经批准了四种 DOAC（达比加群酯、利伐沙班、阿哌沙班和依度沙班），它们旨在克服 VKA 的实际局限性。本综述总结了 DOAC 的生物药剂学考虑因素，通过风险分析对这些药物进行进一步分类，根据生物药剂学分类系统（BCS）进行了批判性讨论。这些讨论包括关于 DOAC 的物理化学性质、平衡溶解度、渗透性和药物溶解的数据。从生物药剂学特征可以确定与吸收过程相关的关键变量，这有助于新制剂的设计。将这些数据与监管机构根据 BCS 推荐的生物药剂学分类标准进行了比较。从这些数据可以看出，基于 BCS 的生物豁免可以讨论通用药物的批准，以及新型 DOAC 制剂带来的临床风险。然而，尽管有 DOAC 的生物药剂学分类的迹象，但根据 BCS 对这些化合物进行分类的结论性信息仍然缺乏，需要更多的实验研究来实现这一目标。结论性信息对于关于生物豁免的安全决策以及指导含有 DOAC 的新制剂的开发至关重要。
