title: Population pharmacokinetics of recombinant factor VIII Fc fusion protein.
abstract: Population pharmacokinetics (PK) of FVIII activity-time profiles following recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor VIII (rFVIII) dosing were evaluated in previously treated patients with severe hemophilia A (from two clinical trials). Potential covariates that may be determinants of variability in FVIII activity were identified. A 2-compartment model adequately described the PK of both compounds. von Willebrand Factor (VWF) concentration was the major covariate for rFVIIIFc clearance, reflecting its protective role in FVIII activity clearance. The effect of body weight and hematocrit on the central volume of distribution of rFVIIIFc was minor. The results of these analyses confirmed that rFVIIIFc clearance (1.65 dL/h) is much lower than that of rFVIII (2.53 dL/h), while the steady state volumes of distribution were similar. The strong positive correlations between the PK parameters of rFVIIIFc and rFVIII suggest that individuals who have high time-related PK characteristics with rFVIII are likely to have comparable characteristics with rFVIIIFc. Steady-state activity-time profiles for selected rFVIIIFc dosing regimens were simulated accounting for uncertainty in model parameters. These population PK analyses and simulations provide a comprehensive characterization of the PK of rFVIIIFc and rFVIII and may be useful for designing dosing regimens.
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Neelakantan
authors.affiliation: Consultant, San Antonio, TX, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ludden
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Li
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Rogge
mesh_terms: D001835:Body Weight; D003198:Computer Simulation; D018592:Cross-Over Studies; D005169:Factor VIII / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006400:Hematocrit; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D006490:Hemostatics; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII
keywords: dosing regimen; hemophilia A; modeling; population pharmacokinetics; recombinant factor VIII Fc fusion protein