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Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII.

AbstractINTRODUCTION:
rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.
MATERIALS AND METHODS:
Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate(®)) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl3-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200-250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.
RESULTS:
rVIII-SingleChain displayed a high affinity for von Willebrand factor (KD=44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl3-induced arterial occlusion model.
CONCLUSIONS:
rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.
AuthorsSabine Zollner, Elmar Raquet, Philipp Claar, Jochen Müller-Cohrs, Hubert J Metzner, Thomas Weimer, Ingo Pragst, Gerhard Dickneite, Stefan Schulte
JournalThrombosis research (Thromb Res) Vol. 134 Issue 1 Pg. 125-31 (Jul 2014) ISSN: 1879-2472 [Electronic] United States
PMID24814969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014. Published by Elsevier Ltd.
Chemical References
  • von Willebrand Factor
  • recombinant factor VIII SQ
  • Factor VIII
Topics
  • Animals
  • Disease Models, Animal
  • Factor VIII (pharmacokinetics, pharmacology)
  • Hemophilia A (metabolism)
  • Macaca fascicularis
  • Mice
  • Rabbits
  • Rats
  • Surface Plasmon Resonance
  • von Willebrand Factor (metabolism)

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