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Rasmussen CE, Nowak J, Larsen JM, et al. Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat. J Toxicol. 2017;2017:8496246doi: 10.1155/2017/8496246.
Rasmussen, C. E., Nowak, J., Larsen, J. M., Moore, E., Bell, D., Liu, K. C., Sorensen, N. S., Kappers, W. A., Krogh-Meibom, T., & Offenberg, H. (2017). Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat. Journal of toxicology, 20178496246. https://doi.org/10.1155/2017/8496246
Rasmussen, Caroline E, et al. "Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat." Journal of toxicology vol. 2017 (2017): 8496246. doi: https://doi.org/10.1155/2017/8496246
Rasmussen CE, Nowak J, Larsen JM, Moore E, Bell D, Liu KC, Sorensen NS, Kappers WA, Krogh-Meibom T, Offenberg H. Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat. J Toxicol. 2017;2017:8496246. doi: 10.1155/2017/8496246. Epub 2017 Mar 28. PMID: 28458688; PMCID: PMC5387834.
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J Toxicol. 2017;2017:8496246. doi: 10.1155/2017/8496246. Epub 2017 Mar 28.

Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat.

Journal of toxicology

Caroline E Rasmussen, Jette Nowak, Julie M Larsen, Emma Moore, David Bell, Kai Chiu Liu, Nanna Skall Sorensen, Wendela A Kappers, Thomas Krogh-Meibom, Hanne Offenberg

Affiliations

  1. Non-Clinical Development, Novo Nordisk A/S, Måløv, Denmark.
  2. Envigo, Huntingdon, UK.

PMID: 28458688 PMCID: PMC5387834 DOI: 10.1155/2017/8496246

Abstract

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.

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