title: Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department for Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum, Berlin Friedrichshain, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Klamroth
authors.affiliation: Rush University Medical Center, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Simpson
authors.affiliation: Werlhof Institut, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Depka-Prondzinski
authors.affiliation: Medical College of Wisconsin and Blood Center of Wisconsin, Milwaukee, WI, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Gill
authors.affiliation: Ospedaliero Universitaria Careggi, Firenze, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Morfini
authors.affiliation: Hemophilia Treatment Center, UC Davis, Sacramento, CA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Powell
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Santagostino
authors.affiliation: University of Miami Hemophilia Treatment Center, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.affiliation: Hämophiliezentrum und Gerinnungsambulanz SRH Kurpfalzkrankenhaus, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Huth-Kühne
authors.affiliation: Louisiana Center for Bleeding and Clotting Disorders, New Orleans, LA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Leissinger
authors.affiliation: Klinische Abteilung für Hämatologie, Medizinische Universität of Graz, Graz, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Neumeister
authors.affiliation: Clinical R&D, CSL Behring, King of Prussia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.affiliation: Clinical R&D, CSL Behring, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Feussner
authors.affiliation: Clinical R&D, CSL Behring, King of Prussia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Limsakun
authors.affiliation: Clinical R&D, CSL Behring, King of Prussia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Clinical R&D, CSL Behring, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Veldman
authors.affiliation: Clinical R&D, CSL Behring, King of Prussia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: St Ledger
authors.affiliation: Clinical R&D, CSL Behring, King of Prussia, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Blackman
authors.affiliation: Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. ingrid.pabinger@meduniwien.ac.at.
authors.forename: I
authors.initials: I
authors.lastname: Pabinger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood; D019540:Area Under Curve; D001780:Blood Coagulation Tests; D003029:Coagulants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005169:Factor VIII / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D003029:Coagulants; C078147:F8 protein, human; D005169:Factor VIII
keywords: clearance; factor VIII; haemophilia A; half-life; pharmacokinetics; von Willebrand factor