title: Prediction of Warfarin Dose in Pediatric Patients: An Evaluation of the Predictive Performance of Several Models.
abstract: OBJECTIVE
  The objective of this study was to evaluate the performance of pediatric pharmacogenetic-based dose prediction models by using an independent cohort of pediatric patients from a multicenter trial.
  
  
  METHODS
  Clinical and genetic data (CYP2C9 [cytochrome P450 2C9] and VKORC1 [vitamin K epoxide reductase]) were collected from pediatric patients aged 3 months to 17 years who were receiving warfarin as part of standard care at 3 separate clinical sites. The accuracy of 8 previously published pediatric pharmacogenetic-based dose models was evaluated in the validation cohort by comparing predicted maintenance doses to actual stable warfarin doses. The predictive ability was assessed by using the proportion of variance (R(2)), mean prediction error (MPE), and the percentage of predictions that fell within 20% of the actual maintenance dose.
  
  
  RESULTS
  Thirty-two children reached a stable international normalized ratio and were included in the validation cohort. The pharmacogenetic-based warfarin dose models showed a proportion of variance ranging from 35% to 78% and an MPE ranging from -2.67 to 0.85 mg/day in the validation cohort. Overall, the model developed by Hamberg et al showed the best performance in the validation cohort (R(2) = 78%; MPE = 0.15 mg/day) with 38% of the predictions falling within 20% of observed doses.
  
  
  CONCLUSIONS
  Pharmacogenetic-based algorithms provide better predictions than a fixed-dose approach, although an optimal dose algorithm has not yet been developed.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Marek
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Momper
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, City, Milwaukee, Wisconsin.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
authors.affiliation: Division of Cardiology, Children's Hospital of Los Angeles, Los Angeles, California.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Takao
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, City, Milwaukee, Wisconsin.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Gill
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Vera
authors.initials: V
authors.lastname: Pravica
authors.affiliation: Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Pediatric Clinical Pharmacology Staff, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
authors.affiliation: Section of Pharmacology & Toxicology, University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, Arkansas.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
keywords: children; pediatrics; pharmacogenetics; warfarin