Journal article
Enhancing the pharmacokinetic properties of recombinant factor VIII: first‐in‐human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A
Journal of thrombosis and haemostasis, Vol.11(4), pp.670-678
04/2013
DOI: 10.1111/jth.12161
PMID: 23398640
Abstract
Summary
Background
N8‐GP is a recombinant factor VIII (FVIII) with a site‐directed glycoPEGylation for the purpose of half‐life prolongation.
Objectives
To evaluate the safety and pharmacokinetic profiles of N8‐GP in comparison with those of the patients' previous FVIII products.
Patients/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.
Details
- Title: Subtitle
- Enhancing the pharmacokinetic properties of recombinant factor VIII: first‐in‐human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A
- Creators
- A Tiede - Hannover Medical SchoolB Brand - University Hospital ZurichR Fischer - Universities of Giessen and Marburg Lung CenterK Kavakli - Ege University Children's HospitalS. R Lentz - The University of IowaT Matsushita - Nagoya University HospitalC Rea - St Thomas' HospitalK Knobe - Novo Nordisk A/SD Viuff - Novo Nordisk A/S
- Resource Type
- Journal article
- Publication Details
- Journal of thrombosis and haemostasis, Vol.11(4), pp.670-678
- DOI
- 10.1111/jth.12161
- PMID
- 23398640
- NLM abbreviation
- J Thromb Haemost
- ISSN
- 1538-7933
- eISSN
- 1538-7836
- Number of pages
- 9
- Language
- English
- Date published
- 04/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094346902771
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