title: Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Product Development, CSL Behring AG, CH-3000 Bern, Switzerland. Electronic address: Sabine.Zollner@cslbehring.com.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zollner
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Raquet
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Claar
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Müller-Cohrs
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Hubert J
authors.initials: HJ
authors.lastname: Metzner
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimer
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.affiliation: Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005169:Factor VIII / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006467:Hemophilia A / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D011817:Rabbits; D051381:Rats; D020349:Surface Plasmon Resonance; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; C427184:recombinant factor VIII SQ; D005169:Factor VIII
keywords: Animal models; Coagulation factors; Haemophilia A/B; Haemophilia therapy; von Willebrand factor