Rasmussen Caroline E, Nowak Jette, Larsen Julie M, Moore Emma, Bell David, Liu Kai Chiu, Sorensen Nanna Skall, Kappers Wendela A, Krogh-Meibom Thomas, Offenberg Hanne
Non-Clinical Development, Novo Nordisk A/S, Måløv, Denmark.
Envigo, Huntingdon, UK.
J Toxicol. 2017;2017:8496246. doi: 10.1155/2017/8496246. Epub 2017 Mar 28.
Turoctocog alfa pegol (N8-GP) is a glycoPEGylated human recombinant factor VIII for the treatment of hemophilia A. The safety profile of rFVIII, and polyethylene glycols (PEG) technology, is well-established. Conducting long-term toxicity studies in animals using human proteins can be complicated by anti-drug antibody (ADA) development. To evaluate long-term safety of N8-GP, 26- and 52-week toxicity studies were conducted in immune-deficient rats dosed intravenously every fourth day with 0, 50, 150, 500, or 1200 IU/kg N8-GP. Observations included clinical observations, body weight, ophthalmoscopy, hematology, chemistry, coagulation, urinalysis, toxicokinetics, antibody analysis, and macroscopic/microscopic organ examination. Immunohistochemical staining examined the distribution of PEG in the brain. No adverse test item-related findings were seen and PEG was not detected in the brain. Exposure was confirmed for ~75% of the animals dosed with 500 and 1200 IU/kg N8-GP; the high lower limit of quantification of the bioanalysis assay prevented confirmation of exposure in the lower doses. A small number of animals developed ADAs, and the proportion of animals surviving until scheduled termination was >80%. N8-GP was well tolerated, and the immune-deficient rat proved suitable for testing long-term toxicity of human proteins that are immunogenic in animals.
聚乙二醇化重组人凝血因子VIII（N8-GP）是一种用于治疗A型血友病的糖基化聚乙二醇化人重组凝血因子VIII。重组凝血因子VIII和聚乙二醇（PEG）技术的安全性已得到充分证实。使用人类蛋白质在动物中进行长期毒性研究可能会因抗药物抗体（ADA）的产生而变得复杂。为了评估N8-GP的长期安全性，对免疫缺陷大鼠进行了26周和52周的毒性研究，每四天静脉注射0、50、150、500或1200 IU/kg的N8-GP。观察指标包括临床观察、体重、眼科检查、血液学、化学、凝血、尿液分析、毒代动力学、抗体分析以及大体/显微镜下器官检查。免疫组织化学染色检测了PEG在脑中的分布。未发现与试验项目相关的不良发现，且在脑中未检测到PEG。对于500和1200 IU/kg N8-GP剂量组中约75%的动物确认有药物暴露；生物分析测定的高定量下限阻止了低剂量组药物暴露的确认。少数动物产生了ADA，存活至预定终止时间的动物比例>80%。N8-GP耐受性良好，免疫缺陷大鼠被证明适用于测试在动物中具有免疫原性的人类蛋白质的长期毒性。
