Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Mainz, Germany.
Nephrology and Kidney Transplant Medicine, Asian Institute of Medical Sciences, Faridabad, NCR, India.
Eur J Pharm Biopharm. 2024 Oct;203:114426. doi: 10.1016/j.ejpb.2024.114426. Epub 2024 Jul 26.
The complex nature of intravenous (IV) iron formulations makes manufacturing and characterising similars challenging. This study examined whether simple in vitro tests can distinguish the high-dose IV iron formulation, Monofer® (ferric derisomaltose [FDI]), from the first intended copies of FDI, Rapifer® (FDI intended similar A [FDIIS-A]) and Tosiron® (FDI intended similar B [FDIIS-B]), approved in India and Pakistan, respectively. Neither intended similar is available in Europe or the United States.
Iron content, pH, density, non-volatile residue, carbohydrate content, molecular weight distribution, complex robustness (measured using acid hydrolysis half-life [t]) and free (dialysable) iron content were examined. Mean results from three batches of FDIIS-A were compared with mean values calculated from three batches of Monofer®. Due to product withdrawal, only one batch of FDIIS-B was available for comparison with Monofer®.
Iron content was similar for all formulations (∼100 mg/mL). The chromatograms (obtained using gel permeation chromatography) of FDIIS-A and FDIIS-B differed from that of Monofer®. FDIIS-A was substantially less robust than Monofer® (t: 15 h versus 40.3 h); t for FDIIS-B was not tested. Free iron content was substantially higher in FDIIS-A (0.091 % w/v) and FDIIS-B (1.0 % w/v) versus Monofer® (<0.003 % w/v). Where tested, remaining parameters varied between the formulations (insufficient sample quantities prevented all tests being conducted for all intended similars). For all tests, greater inter-batch variability was seen for FDIIS-A versus Monofer®.
Simple in vitro tests demonstrated that, aside from total iron content, the first intended similars of FDI bear little resemblance to their originator drug. It is clear that the efficacy and safety profile of Monofer® cannot be extrapolated to the two intended similars. The results call for increased regulatory scrutiny of intended IV iron similars.
静脉注射（IV）铁制剂的复杂性使得制造和表征类似物具有挑战性。本研究旨在探讨简单的体外试验是否能够区分高剂量 IV 铁制剂 Monofer®（ferric derisomaltose [FDI]）与在印度和巴基斯坦分别获得批准的 FDI 的首批仿制药物 Rapifer®（FDI intended similar A [FDIIS-A]）和 Tosiron®（FDI intended similar B [FDIIS-B]）。这两种仿制药物均未在欧洲或美国上市。
检测了铁含量、pH 值、密度、非挥发性残渣、碳水化合物含量、分子量分布、络合物稳定性（使用酸水解半衰期 [t] 测量）和游离（可透析）铁含量。将三个批次的 FDIIS-A 的平均值与三个批次的 Monofer®的平均值进行比较。由于产品撤回，只有一个批次的 FDIIS-B 可与 Monofer®进行比较。
所有制剂的铁含量相似（约 100mg/mL）。FDIIS-A 和 FDIIS-B 的色谱图（使用凝胶渗透色谱法获得）与 Monofer®的色谱图不同。FDIIS-A 的稳定性明显低于 Monofer®（t：15 小时对 40.3 小时）；未对 FDIIS-B 的 t 值进行测试。FDIIS-A（0.091%w/v）和 FDIIS-B（1.0%w/v）的游离铁含量明显高于 Monofer®（<0.003%w/v）。在进行测试的情况下，制剂之间的其他参数也有所不同（由于样本数量不足，无法对所有仿制药物进行所有测试）。对于所有测试，FDIIS-A 与 Monofer®相比，批间变异性更大。
简单的体外试验表明，除了总铁含量外，FDI 的首批仿制药物与其原研药物几乎没有相似之处。显然，Monofer®的疗效和安全性不能外推到这两种仿制药物。结果呼吁加强对静脉注射铁仿制药物的监管审查。
