Predictions of warfarin exposure and INR response in children
A-K Hamberg (1), M Wadelius (1), H Takahashi (2), LE Friberg (3), EN Jonsson (3)(4)
(1) Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden, (2) Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan, (3) Department of Pharmaceutical Biosciences, Uppsala University, Sweden, (4) Exprimo NV, Mechelen, Belgium
Background: Warfarin therapy is challenging due to its narrow therapeutic range and pronounced inter-individual variability in dose requirements. Numerous studies have investigated causes of dose variability in adults, but there is still a paucity of data from warfarin treated children. It has been suggested that the PK in children ≥ 2 years in general can be predicted from prior information on adult PK parameters and body-weight adjustment. Hence, the main challenge with regard to dosing in children is to elucidate whether the PKPD relationship differs between adults and children [1]. We have published a population model for warfarin in adults [2], which after minor revisions could form the starting point for a pharmacometric model applicable to both adults and children.
Objectives: To assess whether allometric weight scaling of a published population model for warfarin can predict exposure and INR response in children.
Methods: The published PK and KPD models were adapted for allometric scaling by weight. The revised models were used to predict a sparse PKPD dataset from 52 Japanese children aged 1-18 years old that were genotyped for CYP2C9 (*1/*1 n=45, *1/*3 n=7) but not for VKORC1 [3]. When predicting INR, all children were assumed to be VKORC1 A/A, the dominant genotype (>80%) among Asians. VPCs were used to assess the predictive performance of the models [4] in both adults and children.
Results: The PK model performed well in the prediction of S-warfarin exposure in Japanese children aged 1-18 years old. Preliminary results with the KPD model also indicate a reasonably good agreement between predicted and observed INR response in children.
Conclusions: Allometricly scaled models developed from adult data appear to be a viable approach to overcome the paucity of warfarin data in children and should prove useful as a basis for individualised dosing recommendations in children. Additional data from warfarin treated children from all phases of therapy, especially start of treatment, and from different ethnic groups with diverse genetic profiles, are warranted for further evaluation of the predictive performance of the KPD model in children.
References:
[1] Holford N. Clin Pharmacol Ther. 2010 Mar;87(3):367-70
[2] Hamberg A-K. et al. Clin Pharmacol Ther. 2010;87(6):727-34
[3] Takahashi H. et al. Clin Pharmacol Ther. 2000;68(5):541-55
[4] Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. AAPS J. 2011 Feb 8. [Epub ahead of print]
