title: Characterizing variability in warfarin dose requirements in children using modelling and simulation.
abstract: OBJECTIVE
  Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.
  
  
  METHODS
  Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimize a published adult pharmacometric warfarin model for use in children.
  
  
  RESULTS
  Genotype effects in children were found to be comparable with what has been reported for adults, with CYP2C9 explaining up to a four-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a two-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a three-fold difference in dose for a four-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.
  
  
  CONCLUSIONS
  The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting on warfarin dose variability in children. With this new knowledge more individualized dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.
authors: Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
authors: Anna-Karin
authors: AK
authors: Hamberg
authors: Mia
authors: M
authors: Wadelius
authors: Lena E
authors: LE
authors: Friberg
authors: Tina T
authors: TT
authors: Biss
authors: Farhad
authors: F
authors: Kamali
authors: E Niclas
authors: EN
authors: Jonsson
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D019934:International Normalized Ratio; D008297:Male; D008954:Models, Biological; D064887:Observational Studies as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013997:Time Factors; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: PKPD modelling; dose variability; paediatrics; pharmacogenetics; pharmacometrics; warfarin