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

Abstract

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.

Fig. 1

Schematic picture of the PK/PD-based population model for warfarin

Fig. 2

Prediction corrected VPC for the bridged KPD model applied on data from warfarin-treated adults. The solid line denote the median of observed data (circles) and dotted lines denote the 2.5^th and 97.5^th percentiles of observed data. Shaded areas represent 95 % confidence intervals of simulated 95 % prediction intervals and medians

Fig. 3

Prediction corrected VPCs for the bridged KPD model applied on data from warfarin-treated children. The panel to the left represent data from all children (n = 64) and the three panels to the right are after stratification of data into three age groups; ≤ 2 years, > 2 and <8 years and ≥ 8 years. Solid lines denote the medians of observed data (circles) and dotted lines denote the 5^th and 95^th percentiles of observed data. Shaded areas represent 95 % confidence intervals of simulated 90 % prediction intervals and medians

Fig. 4

Percent prediction error in warfarin maintenance dose in children 0–18 years old. Results are provided as % prediction error in a priori predicted maintenance dose for one non-pharmacogenetic (empiric 0.2 mg/kg dose) and four pharmacogenetics-based algorithms, and in a posteriori predicted maintenance dose for the bridged KPD model. Results from the different models included in the comparison are connected for each child. Results above zero means that the dose was overpredicted and results below zero that the dose was underpredicted