Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A
Version of Record online: 11 APR 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 4, pages 670–678, April 2013
How to Cite
Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 2013; 11: 670–8., , , , , , , , .
- Issue online: 11 APR 2013
- Version of Record online: 11 APR 2013
- Accepted manuscript online: 11 FEB 2013 05:49AM EST
- Manuscript Accepted: 30 JAN 2013
- Manuscript Received: 12 NOV 2012
- half-life prolongation;
- hemophilia A;
- PEG ;
N8-GP is a recombinant factor VIII (FVIII) with a site-directed glycoPEGylation for the purpose of half-life prolongation.
To evaluate the safety and pharmacokinetic profiles of N8-GP in comparison with those of the patients' previous FVIII products.
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).
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.
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.