Therapeutic dosing of acenocoumarol: proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians.
OBJECTIVE
To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction.


METHODS
Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1 -1639 G>A, CYP4F2 1347 G>A, CYP2C9*2,*3 and GGCX 12970 C>G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated.


RESULTS
The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4% (p-value <0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under-estimation in comparison to clinical data. The VKORC1-1639 G>A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model.


CONCLUSIONS
We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm which might become a baseline for personalised medicine approach for treatment of patients in future.
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
Saurabh Singh
SS
Rathore
Surendra Kumar
SK
Agarwal
Shantanu
S
Pande
Sushil Kumar
SK
Singh
Tulika
T
Mittal
Balraj
B
Mittal
D000074:Acenocoumarol / Q000008:administration & dosage* / Q000627:therapeutic use; D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D001778:Blood Coagulation Disorders / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results
D000925:Anticoagulants; D000074:Acenocoumarol