A patient on warfarin for atrial fibrillation has a CYP2C9*2/*3 genotype and VKORC1 -1639A/A genotype. Compared to a patient with wild-type alleles, this patient would require:

• A Higher warfarin dose due to increased CYP2C9 metabolism
• B The same dose with more frequent INR monitoring
• C Significantly lower warfarin dose due to reduced warfarin metabolism (CYP2C9*3) AND increased VKORC1 sensitivity to warfarin ✓
• D Higher dose because VKORC1 A/A variant requires more drug to achieve inhibition

Explanation

Two independent pharmacogenomic factors combine to dramatically increase warfarin sensitivity: (1) CYP2C9*2 and *3 variant alleles encode enzymes with reduced catalytic activity (~50% and ~10% of wild-type respectively), reducing S-warfarin metabolism and increasing plasma half-life; (2) VKORC1 -1639A variant (particularly in homozygous form A/A) reduces VKORC1 enzyme expression by ~75%, meaning far less warfarin is needed to inhibit the target. Patients with both CYP2C9*3/*3 and VKORC1 A/A may require only 20–25% of the average warfarin dose to maintain therapeutic INR. The FDA-approved warfarin labeling now includes pharmacogenomics-based dosing algorithms using these genotypes.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.