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

Abstract

PurposeNumerous 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.MethodAn 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.ResultsOverall, 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 %.ConclusionA mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-012-1466-4) contains supplementary material, which is available to authorized users.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics‐Guided Warfarin Dosing: 2017 Update

“…Furthermore, there are no data in children that included CYP2C9*5 , *6 , *8 , or *11 genotyping. Based on the current evidence, in children of European ancestry and if CYP2C9 * 2 and *3 and VKORC1-1639 genotype are available, calculate warfarin dosing based on a validated published pediatric pharmacogenetic algorithm (Figure 3) (40, 41). A dosing tool that can be used in children of European ancestry is available at http://www.warfarindoserevision.com (42).…”

Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: A systematic review and meta‐analysis

“…Moreover, a dosing algorithm for adult patients has been established by the US Food and Drug Administration and International Warfarin Pharmacogenetics Consortium . However, due to several factors,the pharmacogenetic model for adults cannot be directly used for pediatric patients, and need for pediatric‐focused pharmacogenomic studies . One is that the maturation of metabolic enzymes, which is age‐related, has a significant effect on warfarin dose requirements .…”

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy

“…[42][43][44][45][46] We recommend using the model developed by Biss et al, as the accuracy of this model has been validated using retrospective data in replication cohorts. 44,47,48 To date, none of the pediatric dosing algorithms have been evaluated in prospective cohorts and are not available as a ready-to-use computer/phone application or Web site. Alternatively, the IWPC model has also been shown to be predictive of maintenance dose in children, although it is less accurate compared with pediatric-derived pharmacogenetic dosing models.…”