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 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. © 2017 caroline e. rasmussen et al.