2. Academic Validation
  3. Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A

  • Haemophilia. 2016 Sep;22(5):730-8. doi: 10.1111/hae.12985.
R Klamroth 1,  M Simpson 2,  M von Depka-Prondzinski 3,  J C Gill 4,  M Morfini 5,  J S Powell 6,  E Santagostino 7,  J Davis 8,  A Huth-Kühne 9,  C Leissinger 10,  P Neumeister 11,  D Bensen-Kennedy 12,  A Feussner 13,  T Limsakun 12,  M Zhou 12,  A Veldman 13,  K St Ledger 12,  N Blackman 12,  I Pabinger 14
Affiliations

Affiliations

  • 1 Department for Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum, Berlin Friedrichshain, Germany.
  • 2 Rush University Medical Center, Chicago, IL, USA.
  • 3 Werlhof Institut, Hannover, Germany.
  • 4 Medical College of Wisconsin and Blood Center of Wisconsin, Milwaukee, WI, USA.
  • 5 Ospedaliero Universitaria Careggi, Firenze, Italy.
  • 6 Hemophilia Treatment Center, UC Davis, Sacramento, CA, USA.
  • 7 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
  • 8 University of Miami Hemophilia Treatment Center, Miami, FL, USA.
  • 9 Hämophiliezentrum und Gerinnungsambulanz SRH Kurpfalzkrankenhaus, Heidelberg, Germany.
  • 10 Louisiana Center for Bleeding and Clotting Disorders, New Orleans, LA, USA.
  • 11 Klinische Abteilung für Hämatologie, Medizinische Universität of Graz, Graz, Austria.
  • 12 Clinical R&D, CSL Behring, King of Prussia, PA, USA.
  • 13 Clinical R&D, CSL Behring, Marburg, Germany.
  • 14 Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. [email protected].
PMID: 27434619 DOI: 10.1111/hae.12985
Abstract

Background: rVIII-SingleChain, a novel recombinant Factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII.

Aim: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII.

Methods: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products.

Results: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported.

Conclusions: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Keywords

clearance; factor VIII; haemophilia A; half-life; pharmacokinetics; von Willebrand factor.

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