Warfarin Stable Dose Prediction Formula And Dosage Associated Mutatons Study

Warfarin is the most widely prescribed coumarin anticoagulant for prevention and treatment of vascular thromboembolic diseases. The pharmacological effect of warfarin is by inhibiting the Vitamin K cycle. Warfarin has been evidenced been metabolismed by Cytochrome P450enzymes and then been eliminated by the kidney. The characteristics of warfarin clinical use as follow:narrow therapeutic window, serious adverse effects, big individual differences and so on. The reasons of big warfarin individual differnce is complex and imcompletely understood, anticoagulant therapy is complicated by numerous factors. It is widely accepted that discrepance of WSD mainly as the result of heritable variation, and the most powerful polymorphisms located in the drug target (VKORC1) and mian drug metabolic enzyme (CYP2C9), which together and explain about40%of warfarin interindividual difference.The Amercia FDA has noted that patients should identify the mutation of CYP2C9and VKORC1before treatment, and then predict a initial therapy dose by the IWPS algorithm in order to reduce the rate of adverse effects and the time to reach stable dose. Howerve, the WSD has big inter-ethic difference, the dailly dose of Caucasus and Africa populations were significantly higher than Cinese population. Hence, we expect to explore a new warfarin dose predict algorithm for Chinese patients.Furthermore, we plain to implet the second generation sequence method to explore other genetic factors which can also explain warfarin interindividual difference to some extent except the contribution of CYP2C9and VKORC1. And further develop a new dose prediction method for high dose and low dose patients, whom at a high risk of adverse effects.The main results of our research as follow:1. We established a new warfarin pharmacogenetics dose predictive model, which can explain36.1%warfarin interindividual difference and the forecast accuracy is56.2%, and the prediction accuracy for patients with dose between1.88-4mg/day is68%.2. We found some new warfarin dose related mutations in warfarin candicate genes except the variations of CYP2C9and VKORC1. And we use five classification approaches of the data mining method successfully devide high dose and low dose patients, the predicton accuracy were higher than60%.