title: Development of a novel individualized warfarin dose algorithm based on a population pharmacokinetic model with improved prediction accuracy for Chinese patients after heart valve replacement.
abstract: The gene-guided dosing strategy of warfarin generally leads to over-dose in patients at doses lower than 2 mg/kg, and only 50% of individual variability in daily stable doses can be explained. In this study, we developed a novel population pharmacokinetic (PK) model based on a warfarin dose algorithm for Han Chinese patients with valve replacement for improving the dose prediction accuracy, especially in patients with low doses. The individual pharmacokinetic (PK) parameter - apparent clearance of S- and R-warfarin (CLs) was obtained after establishing and validating the population PK model from 296 recruited patients with valve replacement. Then, the individual estimation of CLs, VKORC1 genotypes, the steady-state international normalized ratio (INR) values and age were used to describe the maintenance doses by multiple linear regression for 144 steady-state patients. The newly established dosing algorithm was then validated in an independent group of 42 patients and was compared with other dosing algorithms for the accuracy and precision of prediction. The final regression model developed was as follows: Dose=-0.023×AGE+1.834×VKORC1+0.952×INR+2.156×CLs (the target INR value ranges from 1.8 to 2.5). The validation of the algorithm in another group of 42 patients showed that the individual variation rate (71.6%) was higher than in the gene-guided dosing models. The over-estimation rate in patients with low doses (<2 mg/kg) was lower than the other dosing methods. This novel dosing algorithm based on a population PK model improves the predictive performance of the maintenance dose of warfarin, especially for low dose (<2 mg/d) patients.
authors.affiliation: Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
authors.forename: Yu-Bin
authors.initials: YB
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.|School of Clinical Pharmacy, China Pharmaceutical University, Nanjing 210002, China.
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Hong
authors.affiliation: Department of Pharmacy, Jinling Hospital Affiliated to Medical School of Nanjing University, Nanjing 210000, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.|School of Clinical Pharmacy, China Pharmaceutical University, Nanjing 210002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
authors.forename: Shu-Kui
authors.initials: SK
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Zhu
authors.affiliation: School of Clinical Pharmacy, China Pharmaceutical University, Nanjing 210002, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.affiliation: Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210002, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin