title: Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels.
abstract: BACKGROUND
  Routine prophylaxis with replacement factor VIII (FVIII) - the standard of care for severe hemophilia A - often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A.
  
  
  OBJECTIVE
  In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens.
  
  
  METHODS
  We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed.
  
  
  RESULTS
  As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL(-1) (1%) with rFVIIIFc than with equivalent rFVIII regimens.
  
  
  CONCLUSIONS
  These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL(-1) than with rFVIII products requiring more frequent dosing regimens.
authors.affiliation: Department of Hematology, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Shapiro
authors.forename: M V
authors.initials: MV
authors.lastname: Ragni
authors.forename: R
authors.initials: R
authors.lastname: Kulkarni
authors.forename: J
authors.initials: J
authors.lastname: Oldenberg
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.forename: D V
authors.initials: DV
authors.lastname: Quon
authors.forename: K J
authors.initials: KJ
authors.lastname: Pasi
authors.forename: H
authors.initials: H
authors.lastname: Hanabusa
authors.forename: I
authors.initials: I
authors.lastname: Pabinger
authors.forename: J
authors.initials: J
authors.lastname: Mahlangu
authors.forename: P
authors.initials: P
authors.lastname: Fogarty
authors.forename: D
authors.initials: D
authors.lastname: Lillicrap
authors.forename: S
authors.initials: S
authors.lastname: Kulke
authors.forename: J
authors.initials: J
authors.lastname: Potts
authors.forename: S
authors.initials: S
authors.lastname: Neelakantan
authors.forename: I
authors.initials: I
authors.lastname: Nestorov
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: J A
authors.initials: JA
authors.lastname: Dumont
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: A
authors.initials: A
authors.lastname: Brennan
authors.forename: G F
authors.initials: GF
authors.lastname: Pierce
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D003029:Coagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005169:Factor VIII / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D003029:Coagulants; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D014841:von Willebrand Factor; D005169:Factor VIII
keywords: administration schedule; drug; factor VIII; hemophilia A; pharmacokinetics; recombinant fusion proteins