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Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX.

Collins, P W; Møss, J; Knobe, Karin LU ; Groth, A; Colberg, T and Watson, E (2012) In Journal of Thrombosis and Haemostasis 10(11). p.2305-2312
Abstract
Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: 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 every third day). Plasma activity following dosing with N9-GP, rFIX, and pdFIX for surgery and on-demand... (More)
Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: 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 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 N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U/dL, while 40 U/kg once weekly predicted values of 72 and 17 U/dL, respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU/dL for rFIX, and mean values of 43 and 2.1 IU/dL for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP versus 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. © 2012 International Society on Thrombosis and Haemostasis. (Less)
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author
organization
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Contribution to journal
publication status
published
subject
in
Journal of Thrombosis and Haemostasis
volume
10
issue
11
pages
2305 - 2312
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000310548400012
  • pmid:22998153
  • scopus:84868152441
ISSN
1538-7933
DOI
10.1111/jth.12000
language
English
LU publication?
yes
id
1658a391-8f9d-4a64-bb9e-e44b703a22bb (old id 3123802)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22998153?dopt=Abstract
date added to LUP
2012-10-03 22:30:58
date last changed
2017-11-19 04:17:00
@article{1658a391-8f9d-4a64-bb9e-e44b703a22bb,
  abstract     = {Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: 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 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 N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U/dL, while 40 U/kg once weekly predicted values of 72 and 17 U/dL, respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU/dL for rFIX, and mean values of 43 and 2.1 IU/dL for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP versus 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. © 2012 International Society on Thrombosis and Haemostasis.},
  author       = {Collins, P W and Møss, J and Knobe, Karin and Groth, A and Colberg, T and Watson, E},
  issn         = {1538-7933},
  language     = {eng},
  number       = {11},
  pages        = {2305--2312},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX.},
  url          = {http://dx.doi.org/10.1111/jth.12000},
  volume       = {10},
  year         = {2012},
}