Hemophilia Center, General Medicine, Padua University Hospital, Padua, Italy.
Center for Hemorrhagic and Thrombotic Diseases, IRCCS A. Gemelli University Hospital Foundation, Rome, Italy.
Blood Transfus. 2023 Sep;21(5):441-451. doi: 10.2450/2023.0235-22. Epub 2023 Jan 26.
Over the last three decades, the continuous evolution of recombinant factor VIII (rFVIII) concentrates for replacement treatment of hemophilia A, including recent extended half-life products, implies that patients may switch from one product to another, technologically more advanced, with the aim of improving treatment efficacy, safety, management and, ultimately, quality of life. In this scenario, the issues of bioequivalence of rFVIII products and the clinical implications of their interchangeability are keenly debated, in particular when economic reasons or purchasing systems influence product availability and choices. Although sharing the same Anatomical Therapeutic Chemical (ATC) level, rFVIII concentrates, as other biological products, show relevant differences in terms of molecular structure, source and manufacturing process, which make them unique products, recognized as new active substances by regulatory agencies. Moreover, data from clinical trials with both standard and extended half-life products clearly document the large inter-patient variability of pharmacokinetic profiles after administering the same dose of the same product; in cross-over evaluations, even when mean values are comparable, some patients show better patterns with one product or with the comparator one. Pharmacokinetic assessment thus reflects the response to a specific product in the individual patient, with his genetic determinants, only partially identified, affecting the behavior of exogenous FVIII. These concepts, consistent with the currently recommended approach of personalization of prophylaxis, are discussed in this position paper endorsed by the Italian Association of Hemophilia Centers (AICE), highlighting that ATC or other available classifications do not completely consider differences between drugs and innovations and that substitutions of rFVIII products will not invariably ensure the previously achieved clinical outcomes or generate benefits for all patients.
在过去的三十年中，重组凝血因子 VIII（rFVIII）浓缩物的不断发展，用于替代治疗甲型血友病，包括最近的延长半衰期产品，这意味着患者可能会从一种产品切换到另一种技术更先进的产品，以提高治疗效果、安全性、管理水平，并最终提高生活质量。在这种情况下，rFVIII 产品的生物等效性问题及其可互换性的临床意义备受争议，尤其是当经济原因或采购系统影响产品的可获得性和选择时。
尽管 rFVIII 浓缩物与其他生物制品共享相同的解剖治疗化学（ATC）水平，但在分子结构、来源和制造工艺方面存在显著差异，这使它们成为独特的产品，被监管机构认定为新的活性物质。此外，标准半衰期和延长半衰期产品的临床试验数据清楚地记录了在给予相同剂量的同一产品后，药代动力学特征的个体间巨大差异；在交叉评估中，即使平均值可以比较，一些患者仍表现出对一种产品或对照产品更好的模式。因此，药代动力学评估反映了个体患者对特定产品的反应，其遗传决定因素仅部分确定，影响外源性 FVIII 的行为。
这些概念与目前推荐的个体化预防方法一致，在本文中进行了讨论，并得到了意大利血友病中心协会（AICE）的认可，强调 ATC 或其他可用的分类法并未完全考虑药物和创新之间的差异，rFVIII 产品的替代也不会始终确保先前达到的临床结果或为所有患者带来益处。
