title: Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A.
abstract: BACKGROUND
  N8-GP is a recombinant factor VIII (FVIII) with a site-directed glycoPEGylation for the purpose of half-life prolongation.
  
  
  OBJECTIVE
  To evaluate the safety and pharmacokinetic profiles of N8-GP in comparison with those of the patients' previous FVIII products.
  
  
  METHODS
  This dose-escalation trial included previously treated patients with severe hemophilia A who received one of three dose levels (25, 50 or 75 U kg(-1) ) of N8-GP and FVIII product. Each dose escalation was preceded by safety and pharmacokinetic assessment. The trial was registered at www.clinicaltrials.gov (NCT01205724).
  
  
  RESULTS
  Twenty-six patients each received one dose of their previous FVIII product followed by the same, single dose of N8-GP. N8-GP, at any tested dose, was well tolerated, with a low frequency of adverse events. No new inhibitors against FVIII or N8-GP and no binding antibodies against N8-GP developed during the trial. The pharmacokinetics of N8-GP were dose-linear. The incremental recovery of N8-GP was 0.025 [(U mL(-1) )/(U kg(-1) )]. The clearance was 1.79 mL(-1)  h(-1)  kg(-1) . The estimated time from dosing of 50 U kg(-1) N8-GP to a plasma activity of 1% was 6.5 days (range: 3.6-7.9 days). The mean terminal half-life of N8-GP was 19.0 h (range: 11.6-27.3 h), 1.6-fold longer than that of the patients' previous products.
  
  
  CONCLUSIONS
  A single dose of up to 75 U kg(-1) N8-GP was well tolerated in patients with hemophilia A, with no safety concerns. N8-GP had a prolonged half-life, and FVIII:C activity remained at > 1% for longer than the patient's previous product. These results indicate that N8-GP has the potential to reduce dosing frequency during prophylaxis.
authors: Hannover Medical School, Hannover, Germany. Tiede.Andreas@mh-hannover.de
authors: A
authors: A
authors: Tiede
authors: B
authors: B
authors: Brand
authors: R
authors: R
authors: Fischer
authors: K
authors: K
authors: Kavakli
authors: S R
authors: SR
authors: Lentz
authors: T
authors: T
authors: Matsushita
authors: C
authors: C
authors: Rea
authors: K
authors: K
authors: Knobe
authors: D
authors: D
authors: Viuff
mesh_terms: D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry; D011994:Recombinant Proteins / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII