Integration of genetic, clinical, and INR data to refine warfarin dosing.
Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
Lenzini
P
P
Department of Internal Medicine, Washington University, St Louis, Missouri, USA.
Wadelius
M
M
Kimmel
S
S
Anderson
J L
JL
Jorgensen
A L
AL
Pirmohamed
M
M
Caldwell
M D
MD
Limdi
N
N
Burmester
J K
JK
Dowd
M B
MB
Angchaisuksiri
P
P
Bass
A R
AR
Chen
J
J
Eriksson
N
N
Rane
A
A
Lindh
J D
JD
Carlquist
J F
JF
Horne
B D
BD
Grice
G
G
Milligan
P E
PE
Eby
C
C
Shin
J
J
Kim
H
H
Kurnik
D
D
Stein
C M
CM
McMillin
G
G
Pendleton
R C
RC
Berg
R L
RL
Deloukas
P
P
Gage
B F
BF
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods / Q000592:standards*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods; D018511:Systems Integration; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases