CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy.
OBJECTIVE
Variant alleles of the CYP2C9 gene encoding the cytochrome P450 (CYP) enzyme (2C9*2 [Arg144Cys] and 2C9*3 [Ile359Leu]) are known to increase the anticoagulant effect of warfarin and decrease the mean daily dose required to maintain the international normalized ratio (INR) of the prothrombin time within the target therapeutic range. However, little information is available on the effect of CYP2C9 polymorphisms on dose requirements during the most critical step of anticoagulant therapy, the induction phase.


METHODS
This retrospective study evaluated the dosages given to 125 patients who started therapy with warfarin in a clinical center where physicians used the same approach for dosing and frequency of monitoring. CYP2C9 allelic variants were evaluated by polymerase chain reaction followed by restriction enzyme analysis.


RESULTS
From the time of the first INR estimate (day 4) until the end of the induction phase (arbitrarily established at day 24), patients with 2C9*2 or 2C9*3 variant alleles required lower mean daily doses than patients carrying only wild-type alleles 2C9*1 (-17% and -40%, P <.0001). They also more frequently had INR values above the upper limit of the target range (3.0) (65% for 2C9*2/- and 66% for 2C9*3/- versus 33% for 2C9*1/*1; P =.006 and.012, respectively).


CONCLUSIONS
The requirement of smaller doses of warfarin in relation to CYP2C9 polymorphisms is already manifest on the fourth day of treatment, at the time of the first INR estimate. CYP2C9 genotyping is as yet not warranted, but frequent INR monitoring with appropriate dose adjustments is recommended during the first 3 weeks of treatment to avoid overanticoagulation and the inherent risk of bleeding in carriers of variant alleles.
Peyvandi
Flora
F
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Via Pace 9, 20122 Milan, Italy. flora.peyvandi@unimi.it
Spreafico
Marta
M
Siboni
Simona Maria
SM
Moia
Marco
M
Mannucci
Pier Mannuccio
PM
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005787:Gene Frequency / Q000187:drug effects / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000502:physiology; D012189:Retrospective Studies; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases