title: Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.
abstract: Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week.
  
  
  
  Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg-1. PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL-1, at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg-1) and highest (50 IU kg-1) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg-1rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL-1at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios.
authors.affiliation: Clinical Pharmacology and Early Development, CSL Behring, King of Prussia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Pharmacology and Early Development, CSL Behring, King of Prussia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Roberts
authors.affiliation: Clinical Pharmacology and Early Development, CSL Behring, King of Prussia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tortorici
authors.affiliation: Global Clinical Research and Development, CSL Behring GmbH, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Veldman
authors.affiliation: Global Clinical Research and Development, CSL Behring, King of Prussia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: St Ledger
authors.affiliation: Department of Preclinical Research and Development, CSL Behring GmbH, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Feussner
authors.affiliation: Clinical Pharmacology and Early Development, CSL Limited, Parkville, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Sidhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001780:Blood Coagulation Tests; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005169:Factor VIII / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins / Q000493:pharmacokinetics
chemical_list: D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: factor VIII; hemophilia A; pharmacokinetics; recombinant proteins