Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain,a novel recombinant single-chain factor VIII |
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Authors: | Sabine Zollner,Elmar Raquet,Philipp Claar,Jochen Mü ller-Cohrs,Hubert J. Metzner,Thomas Weimer,Ingo Pragst,Gerhard Dickneite,Stefan Schulte |
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Affiliation: | 1. Product Development, CSL Behring AG, CH-3000 Bern, Switzerland;2. Preclinical Research and Development, CSL Behring GmbH, 35041 Marburg, Germany |
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Abstract: | IntroductionrVIII-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 MethodsBinding 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.ResultsrVIII-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.ConclusionsrVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models. |
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Keywords: | AUC, area under the observed average plasma concentration vs. time curve AUC0-last, AUC up to the last quantifiable sampling time CI, confidence interval CL, clearance Cmax, maximum plasma concentration ELISA, enzyme-linked immunosorbent assay FL, full-length FVIII, factor VIII ka, association rate constant KA, association equilibrium constant kd, dissociation rate constant KD, dissociation equilibrium constant MRT, mean residence time KO, knock-out PD, pharmacodynamic pd-VWF, plasma-derived von Willebrand factor PK, pharmacokinetic rFVIII, recombinant factor VIII SD, standard deviation t1/2β, terminal half-life Vd, apparent volume of distribution Vinitial, apparent initial volume of distribution Vss, volume of distribution at steady state VWF, von Willebrand factor |
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