Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE ®) - an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A

U. Martinowitz, J. Bjerre, B. Brand, R. Klamroth, M. Misgav, M. Morfini, E. Santagostino, A. Tiede, D. Viuff

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Abstract

Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate ®, a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50IUkg -1 body weight Advate ® followed by 50IUkg -1 body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate ® and N8 were comparable. The 90% CI for the treatment ratio (Advate ®/N8) for all primary endpoints (incremental recovery, t 1/2, AUC and Cl), and the secondary endpoints (AUC last and C max) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate ®. Furthermore, N8 is well tolerated in the FHD trial.

Original languageEnglish
Pages (from-to)854-859
Number of pages6
JournalHaemophilia
Volume17
Issue number6
DOIs
Publication statusPublished - Nov 2011

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Keywords

  • Bioequivalence
  • First human dose
  • Haemophilia A
  • Open label
  • Pharmacokinetics
  • RFVIII

ASJC Scopus subject areas

  • Hematology
  • Genetics(clinical)
  • Medicine(all)

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