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Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and

D B Hawcutt1, A A Ghani2, L Sutton3

  • 11] Institute of Translational Medicine, University of Liverpool, Liverpool, UK [2] Department of Research, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

The Pharmacogenomics Journal
|July 9, 2014
PubMed

Insights

Pharmacogenetic testing for CYP2C9*2 and VKORC1-1639 can improve warfarin dosing in children. These genetic variations impact time in therapeutic range, dose requirements, and bleeding risk, aiding personalized pediatric care.

Area of Science:

  • Pharmacogenetics
  • Pediatric Pharmacology
  • Clinical Biochemistry

Background:

  • Warfarin dosing in children lacks established pharmacogenetic algorithms.
  • Limited data exists on genetic influences on initial warfarin dosing, therapeutic range, and adverse events in pediatric populations.
  • Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms are known to affect warfarin metabolism and response.

Purpose of the Study:

  • To investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1-1639 polymorphisms on warfarin therapy in children.
  • To identify associations between these genetic variations and time in therapeutic range (INR), initial dosing, stable dose requirements, and bleeding complications.
  • To provide data for the development of pharmacogenomic dosing algorithms for pediatric warfarin use.

Main Methods:

  • A cohort of 97 pediatric participants receiving warfarin was recruited.
  • Routine clinical data and salivary DNA samples were collected.
  • DNA samples were analyzed for CYP2C9*2, CYP2C9*3, and VKORC1-1639 polymorphisms.

Main Results:

  • VKORC1-1639 was associated with a greater proportion of time within the target International Normalised Ratio (INR) range during the first six months of treatment.
  • CYP2C9*2 was linked to a higher likelihood of exceeding the target INR range during treatment initiation.
  • Both CYP2C9*2 and VKORC1-1639 were associated with lower warfarin dose requirements, explaining nearly 12% of stable dose variance.
  • VKORC1-1639 (heterozygotes vs. homozygotes) was associated with an increased likelihood of mild bleeding complications.

Conclusions:

  • Novel associations were found between VKORC1-1639, CYP2C9*2, and INR values in pediatric warfarin patients.
  • These findings replicate previous research on stable warfarin dose requirements.
  • Developing pharmacogenomic dosing algorithms incorporating these genetic markers holds potential for improving warfarin therapy management in children.

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