Warfarin-dosing algorithm based on a population pharmacokinetic/pharmacodynamic model combined with Bayesian forecasting.
OBJECTIVE
To develop a novel warfarin-dosing algorithm based on a previous population pharmacokinetic/pharmacodynamic (PK/PD) model with Bayesian forecasting to facilitate warfarin therapy.


METHODS
Using information on CYP2C9 and VKORC1 genotypes, S-warfarin level, dose and international normalized ratio (INR) of prothrombin time, individual PK (apparent clearance of S-warfarin [CLs]) and PD (concentration resulting in 50% of E(max) [EC(50)]) parameters were determined by Bayesian forecasting for 45 Japanese patients. Maintenance doses were described by multiple linear regression using individually estimated PK/PD parameters and INR values. The validity of the model and a comparison with other dosing methods were evaluated by bootstrap resampling and a cross-validation method.


RESULTS
The plasma concentration of S-warfarin and INR were accurately predicted from individual PK/PD parameters. The following final regression model for maintenance dose was obtained; maintenance dose = 11.2 x CLs + 0.91 x EC(50) + 2.36 x INR - 9.67, giving a strong correlation between actual and predicted maintenance doses (r(2) = 0.944). Bootstrap resampling and cross-validation showed robustness and a superior predictive performance compared with other dosing methods. On the other hand, the predictability without actual measurements (S-warfarin and INR values) and Bayesian inference was comparable to other dosing methods.


CONCLUSIONS
A novel algorithm, based on the population PK/PD model combined with Bayesian forecasting, gave precise predictions of maintenance dose, leading to individualized warfarin therapy.
Sasaki
Tomohiro
T
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Tabuchi
Hiroko
H
Higuchi
Shun
S
Ieiri
Ichiro
I
D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001499:Bayes Theorem; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D007564:Japan; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D008954:Models, Biological; D010597:Pharmacogenetics / Q000379:methods* / Q000706:statistics & numerical data; D011237:Predictive Value of Tests; D012044:Regression Analysis; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000925:Anticoagulants; 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