Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat
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...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2017-01-01
|
| Series: | Journal of Toxicology |
| Online Access: | http://dx.doi.org/10.1155/2017/8496246 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832563880871591936 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Caroline E. Rasmussen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ee7952f1805443caa9153dee89120cad |
| institution | Kabale University |
| issn | 1687-8191 1687-8205 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Toxicology |
| spelling | doaj-art-ee7952f1805443caa9153dee89120cad2025-02-03T01:12:26ZengWileyJournal of Toxicology1687-81911687-82052017-01-01201710.1155/2017/84962468496246Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude RatCaroline E. Rasmussen0Jette Nowak1Julie M. Larsen2Emma Moore3David Bell4Kai Chiu Liu5Nanna Skall Sorensen6Wendela A. Kappers7Thomas Krogh-Meibom8Hanne Offenberg9Non-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkEnvigo, Huntingdon, UKEnvigo, Huntingdon, UKEnvigo, Huntingdon, UKNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkNon-Clinical Development, Novo Nordisk A/S, Måløv, DenmarkTuroctocog 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.http://dx.doi.org/10.1155/2017/8496246 |
| spellingShingle | 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 Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat Journal of Toxicology |
| title | Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat |
| title_full | Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat |
| title_fullStr | Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat |
| title_full_unstemmed | Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat |
| title_short | Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat |
| title_sort | long term safety of pegylated coagulation factor viii in the immune deficient rowett nude rat |
| url | http://dx.doi.org/10.1155/2017/8496246 |
| work_keys_str_mv | AT carolineerasmussen longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT jettenowak longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT juliemlarsen longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT emmamoore longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT davidbell longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT kaichiuliu longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT nannaskallsorensen longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT wendelaakappers longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT thomaskroghmeibom longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat AT hanneoffenberg longtermsafetyofpegylatedcoagulationfactorviiiintheimmunedeficientrowettnuderat |