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Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy
Mark W Linder1, Marjorie Bon Homme, Kristen K Reynolds
1Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Clinical Chemistry
|August 15, 2009
Summary
This study developed a computational tool to guide warfarin dosing using patient genotype and phenotype data. The tool accurately predicts warfarin concentration needed for therapeutic international normalized ratio (INR) response, improving patient care.
Area of Science:
- Pharmacogenomics
- Computational Biology
- Clinical Pharmacology
Background:
- Effective warfarin therapy requires correlating genetic information with clinical action.
- A novel computational decision-support tool was created to integrate patient genotype and phenotype for warfarin dosage guidance.
- This tool estimates pharmacokinetic and pharmacodynamic parameters for warfarin, aiding international normalized ratio (INR) interpretation.
Observation:
- Analysis included 137 patients with stable INRs, examining clinical data, S-warfarin concentrations, and CYP2C9 and VKORC1 genotypes.
- Plasma S-warfarin concentrations were assessed based on VKORC1 genotype (-1639G>A).
- Steady-state S-warfarin concentrations were calculated using CYP2C9 genotype-based clearance rates and compared to actual measurements.
Findings:
- VKORC1 genotype (-1639G>A) significantly correlated with the plasma S-warfarin concentration needed for the target INR response (P < 0.05).
- CYP2C9 genotype modeling predicted 58% of the variation in measured S-warfarin concentration.
- The relationship was described by: Measured [S-warfarin] = 0.67(Estimated [S-warfarin]) + 0.16 mg/L.
Implications:
- VKORC1 genotype predicts the plasma S-warfarin concentration for a therapeutic INR (pharmacodynamics).
- CYP2C9 genotype predicts changes in S-warfarin concentration with repeated dosing (pharmacokinetics).
- Integrating multivariate equations with genotype-guided modeling enhances the clinical utility of CYP2C9 and VKORC1 testing for warfarin management.
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