A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy.
The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.
Hamberg
A-K
AK
Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden. anna-karin.hamberg@roche.com
Dahl
M-L
ML
Barban
M
M
Scordo
M G
MG
Wadelius
M
M
Pengo
V
V
Padrini
R
R
Jonsson
E N
EN
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D015233:Models, Statistical; D010599:Pharmacokinetics; D011153:Population; D013237:Stereoisomerism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D004247:DNA; 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