Key result
Bridged adult KPD model achieves ~70% pediatric warfarin dose accuracy after incorporating INR feedback.
Why the study?
Studies on warfarin dose variability in children are limited in number and size, and there is a need to evaluate adult-based pharmacometric models for pediatric dose prediction.
Does a bridged adult pharmacokinetic/pharmacodynamic model improve warfarin maintenance dose prediction compared to published pediatric algorithms in warfarin-treated children?
Observational (n=64)
Yes
Does a bridged adult pharmacokinetic/pharmacodynamic model improve warfarin maintenance dose prediction compared to published pediatric algorithms in warfarin-treated children?
Absolute Event Rate: 41% vs 41%
A mechanism-based adult population model bridged to children predicted warfarin maintenance doses as accurately as pediatric-specific algorithms, with accuracy improving to 70% when incorporating prior INR observations.
Bridged adult KPD models may inform pediatric warfarin dosing; leaves open prospective validation before clinical use.
PURPOSE: 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. METHOD: 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. RESULTS: 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 ≤2 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 %. CONCLUSION: A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.
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Hamberg et al. (2013) conducted an observational in Children requiring warfarin therapy (n=64). Bridged adult KPD model (pharmacometric bridging) vs. Published pediatric pharmacogenetics-based dosing algorithms was evaluated on Proportion of children with predicted maintenance dose within ±20% of actual dose (ideal dose prediction). The bridged adult KPD model predicted the ideal warfarin maintenance dose a priori in 41% of children (comparable to the best published pediatric algorithm), which increased to 70% when using up to three individual INR observations for a posteriori dose optimization.