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Warfarin dose prediction in children using pharmacometric bridging-comparison with published pharmacogenetic dosing algorithms

Hamberg, Anna-Karin ; Friberg, Lena E. ; Hanséus, Katarina LU ; Ekman-Joelsson, Britt-Marie ; Sunnegardh, Jan ; Jonzon, Anders ; Lundell, Bo ; Jonsson, E. Niclas and Wadelius, Mia (2013) In European Journal of Clinical Pharmacology 69(6). p.1275-1283
Abstract
Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children. An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric... (More)
Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children. An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external data set of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children. Overall, the bridged model predicted INR response well in 64 warfarin-treated Swedish children (median age 4.3 years), but with a tendency to overpredict INR in children a parts per thousand currency sign2 years old. The bridged model predicted 20 of 49 children (41 %) within +/- 20 % of actual maintenance dose (median age 7.2 years). In comparison, the published dosing algorithms predicted 33-41 % of the children within +/- 20 % of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within +/- 20 % of actual dose to 70 %. A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
PK/PD model, Population analysis, Warfarin, Dosing, Children
in
European Journal of Clinical Pharmacology
volume
69
issue
6
pages
1275 - 1283
publisher
Springer
external identifiers
  • wos:000318865600008
  • scopus:84878018047
  • pmid:23307232
ISSN
1432-1041
DOI
10.1007/s00228-012-1466-4
language
English
LU publication?
yes
id
a06e841b-dab9-43c1-8fc0-5fb06203de72 (old id 3932502)
date added to LUP
2016-04-01 13:15:48
date last changed
2020-01-12 11:41:52
@article{a06e841b-dab9-43c1-8fc0-5fb06203de72,
  abstract     = {Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children. An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external data set of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children. Overall, the bridged model predicted INR response well in 64 warfarin-treated Swedish children (median age 4.3 years), but with a tendency to overpredict INR in children a parts per thousand currency sign2 years old. The bridged model predicted 20 of 49 children (41 %) within +/- 20 % of actual maintenance dose (median age 7.2 years). In comparison, the published dosing algorithms predicted 33-41 % of the children within +/- 20 % of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within +/- 20 % of actual dose to 70 %. A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.},
  author       = {Hamberg, Anna-Karin and Friberg, Lena E. and Hanséus, Katarina and Ekman-Joelsson, Britt-Marie and Sunnegardh, Jan and Jonzon, Anders and Lundell, Bo and Jonsson, E. Niclas and Wadelius, Mia},
  issn         = {1432-1041},
  language     = {eng},
  number       = {6},
  pages        = {1275--1283},
  publisher    = {Springer},
  series       = {European Journal of Clinical Pharmacology},
  title        = {Warfarin dose prediction in children using pharmacometric bridging-comparison with published pharmacogenetic dosing algorithms},
  url          = {http://dx.doi.org/10.1007/s00228-012-1466-4},
  doi          = {10.1007/s00228-012-1466-4},
  volume       = {69},
  year         = {2013},
}