A proposal for an individualized pharmacogenetics-based warfarin initiation dose regimen for patients commencing anticoagulation therapy.
A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)days 4-7>4.0 (n=63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction=4.2 mg), whereas in those with mean INRdays 4-7<2.0 (n=145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.
School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UK.
P J
PJ
Avery
A
A
Jorgensen
A K
AK
Hamberg
M
M
Wadelius
M
M
Pirmohamed
F
F
Kamali
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011446:Prospective Studies; D013923:Thromboembolism / Q000188:drug therapy*; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases