China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China.
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Clin Pharmacokinet. 2020 Aug;59(8):995-1004. doi: 10.1007/s40262-020-00889-9.
The interchangeability evaluation for generic drugs formulated as intravenous injections normally only requires assessments of pharmaceutical equivalence (PE) when the medicinal products are simple small-molecule drugs. However, intravenously administered non-biological complex drugs (NBCDs), such as liposomes, microsphere suspension, or fat emulsion, have inherent passive disposition selectivity due to their special formulations, thereby the in vivo drug performances are improved. Because of the complexity in formulation, the in vitro pharmaceutical investigations of follow-on NBCDs are more complicated than those required for generic small-molecule drugs. In addition to qualitative and quantitative sameness of the active and inactive ingredients, it is required to comparatively study the static and kinetic microscopic particle-related physiochemical properties of the follow-on NBCDs versus the reference products. Moreover, for complex formulations that have a significant impact on the biodistribution of the drug compound, an in vivo bioequivalence (BE) study is also important. Since NBCDs that demonstrated bioequivalence through the conventional BE approach have been found inequivalent in efficacy or safety to the reference products, pivotal BE studies for follow-on NBCDs are required to take both encapsulated/total drug and free drug as the analytes to address release kinetics and biodistribution of the active pharmacological ingredient in the body. This manuscript reviews the 26 U.S. FDA published product-specific guidelines for intravenous injections. In general, these NBCDs can be stratified into four groups according to their release kinetics and ability of bio-membrane penetration. Group 1 consists of seven small-molecule, non-complex drugs; group 2 included four NBCDs with either microscale particle size or rapid dissolution property; group 3 include five loosely packed NBCDs (fat emulsions) and one quickly released ophthalmic liposomal drug; and the last group contains four cytotoxic liposomal or protein-bound NBCDs and five iron carbohydrate complexes. The requirements of the corresponding guidelines range from simple proof of PE between the test and the reference products, to a collection of studies that demonstrate the key manufacturing process (e.g. liposome loading), the particle- or vehicle-wise static and kinetic physiological characterizations, the dissolution test, and BE evaluation of both total/encapsulated drug form and free drug form between the follow-on NBCDs and their reference products. Such studies are challenging in implementation. Therefore, a variety of alternative approaches are proposed in this article.
通常情况下，对于作为静脉注射剂的仿制药，仅需要评估其药学等效性（PE），此时药用产品为简单的小分子药物。然而，由于特殊的制剂，静脉给予的非生物复杂药物（NBCD），如脂质体、微球混悬液或脂肪乳剂，具有固有的被动处置选择性，从而改善了体内药物性能。由于制剂的复杂性，后续 NBCD 的体外药物研究比普通小分子药物的研究更为复杂。除了活性和非活性成分的定性和定量相同之外，还需要比较研究后续 NBCD 与参比制剂的静态和动态微观颗粒相关的物理化学性质。此外，对于对药物化合物的生物分布有重大影响的复杂制剂，体内生物等效性（BE）研究也很重要。由于通过常规 BE 方法证明具有生物等效性的 NBCD 在疗效或安全性方面与参比制剂不一致，因此需要对后续 NBCD 进行关键性 BE 研究，以将包裹/总药物和游离药物作为分析物，以解决体内活性药理成分的释放动力学和生物分布。本文综述了美国食品和药物管理局（FDA）发布的 26 项特定于静脉注射剂的产品指南。一般来说，根据其释放动力学和生物膜穿透能力，这些 NBCD 可以分为四类。第 1 组包括 7 种小分子非复杂药物；第 2 组包括 4 种具有微观粒径或快速溶解性质的 NBCD；第 3 组包括 5 种松散包装的 NBCD（脂肪乳剂）和 1 种快速释放的眼用脂质体药物；最后一组包含 4 种细胞毒性脂质体或蛋白结合 NBCD 和 5 种铁碳水化合物复合物。相应指南的要求范围从测试和参比产品之间简单的 PE 证明，到一系列研究，证明关键的制造工艺（例如脂质体负载）、颗粒或载体静态和动态生理特性、溶出度测试以及后续 NBCD 及其参比产品之间总/包裹药物形式和游离药物形式的 BE 评估。这些研究在实施方面具有挑战性。因此，本文提出了多种替代方法。
