title: Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX.
abstract: BACKGROUND
  nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life.
  
  
  OBJECTIVE
  To provide information on potential dose regimens for N9-GP for phase 3 pivotal and surgery trials.
  
  
  METHODS
  A population pharmacokinetic model was developed from single-dose data derived from the first human-dose trial with N9-GP in hemophilia B patients, and was used to extrapolate to steady-state conditions for different N9-GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9-GP with standard prophylactic regimens using rFIX or plasma-derived (pd) FIX (40 IU kg(-1) every third day). Plasma activity following dosing with N9-GP, rFIX and pdFIX for surgery and on-demand treatment of bleeds was also simulated.
  
  
  RESULTS
  A linear two-compartmental model best described the pharmacokinetic profiles of N9-GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg(-1) N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL(-1) , while 40 U kg(-1) once weekly predicted values of 72 and 17 U dL(-1) , respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL(-1) for rFIX, and mean values of 43 and 2.1 IU dL(-1) for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP vs. rFIX and pdFIX for surgery and the treatment of bleeds.
  
  
  CONCLUSIONS
  N9-GP may allow prophylaxis, surgical dosing regimens and on-demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.
authors.affiliation: Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University, Cardiff, UK Clinical Pharmacology Biopharm, Novo Nordisk A/S, Søborg, Denmark Centre for Thrombosis and Haemostasis, Lund University, Malmö, Sweden Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg Medical and Science, Haemophilia, Novo Nordisk A/S, Søborg DMPK and Bioanalysis, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: P W
authors.initials: PW
authors.lastname: Collins
authors.forename: J
authors.initials: J
authors.lastname: Møss
authors.forename: K
authors.initials: K
authors.lastname: Knobe
authors.forename: A
authors.initials: A
authors.lastname: Groth
authors.forename: T
authors.initials: T
authors.lastname: Colberg
authors.forename: E
authors.initials: E
authors.lastname: Watson
mesh_terms: D002408:Catheters, Indwelling; D003198:Computer Simulation; D004334:Drug Administration Schedule; D005164:Factor IX / Q000737:chemistry / Q000493:pharmacokinetics*; D002836:Hemophilia B / Q000188:drug therapy*; D006470:Hemorrhage; D006801:Humans; D020300:Intracranial Hemorrhages / Q000188:drug therapy; D016014:Linear Models; D010599:Pharmacokinetics; D010641:Phenotype; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011788:Quality of Life; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D011994:Recombinant Proteins; C000592276:nonacog beta pegol; D011092:Polyethylene Glycols; D005164:Factor IX