Ling Xue1, Yuzhen Zhang2, Cheng Xie1, Ling Zhou1, Linsheng Liu1, Haiyan Zhang3, Lianhong Xu4, Hongtao Song5, Meiqin Lin5, Hanfan Qiu6, Junrong Zhu7, Yubing Zhu7, Jianjun Zou7, Wenfang Zhuang8, Binbin Xuan9, Yanhong Chen9, Yingchao Fan8, Di Wu10, Zhenya Shen11, Liyan Miao12. 1. Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China. 2. Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China. 3. Department of Pharmacy, the Affiliated Wujin Hospital of Jiangsu University, Changzhou, China. 4. Department of Clinical Laboratory, the Affiliated Wujin Hospital of Jiangsu University, Changzhou, China. 5. Department of pharmacy, Fuzhou General Hospital, Fuzhou, China. 6. Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China. 7. Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China. 8. Department of Laboratory Medicine, East hospital of Yangpu district, Shanghai, China. 9. Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, China. 10. Department of Clinical Pharmacy, the First Affiliated Hospital of Kunming Medical University, Kunming, China. 11. Department of Cardiovascular Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China. uuzyshen@sina.com. 12. Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China. miaolysuzhou@163.com.
Abstract
PURPOSE: The objectives of the study were to establish a dose-response model for warfarin based on the relationship between daily warfarin dose and international normalized ratio (INR) and to evaluate the stability and reliability of the established model using external data. METHODS: Clinical data were recorded from 676 outpatients with a steady-state warfarin dosage. Demographic characteristics, concomitant medications, daily dosage of warfarin, CYP2C9 and VKORC1 genotypes, and INR were recorded. Data analysis based on the Michaelis-Menten equation to describe the relationship between daily warfarin dose and INR was performed using NONMEM. The reliability and stability of the final model were evaluated using goodness-of-fit plots, resampling techniques with a nonparametric bootstrap, and external data. RESULTS: The daily warfarin dose and INR were described by a more pharmacologically expressive model than multivariate linear regression (MLR) model. The population standard value of Km was 3.56 mg, and the Hill coefficient was 0.512, with individual variabilities of 53.1% and 55.9%, respectively. CYP2C9 *1/*3, VKORC1 AA, concomitant amiodarone, and nonheart valve replacement reduced the warfarin Km by 30.4%, 74.3%, 34.5%, and 39.4%, respectively. The Km value decreased with age and increased with fat free mass (FFM). INR prediction error (73.0%) of the external datasets was within ± 20%. CONCLUSION: A dose-response model of warfarin was established based on the relationship between daily warfarin dose and INR. Expected genotype effects on Km and demographic characteristics were confirmed. The model has the potential to be a powerful tool for individualized warfarin therapy for Chinese outpatients.
PURPOSE: The objectives of the study were to establish a dose-response model for warfarin based on the relationship between daily warfarin dose and international normalized ratio (INR) and to evaluate the stability and reliability of the established model using external data. METHODS: Clinical data were recorded from 676 outpatients with a steady-state warfarin dosage. Demographic characteristics, concomitant medications, daily dosage of warfarin, CYP2C9 and VKORC1 genotypes, and INR were recorded. Data analysis based on the Michaelis-Menten equation to describe the relationship between daily warfarin dose and INR was performed using NONMEM. The reliability and stability of the final model were evaluated using goodness-of-fit plots, resampling techniques with a nonparametric bootstrap, and external data. RESULTS: The daily warfarin dose and INR were described by a more pharmacologically expressive model than multivariate linear regression (MLR) model. The population standard value of Km was 3.56 mg, and the Hill coefficient was 0.512, with individual variabilities of 53.1% and 55.9%, respectively. CYP2C9 *1/*3, VKORC1 AA, concomitant amiodarone, and nonheart valve replacement reduced the warfarin Km by 30.4%, 74.3%, 34.5%, and 39.4%, respectively. The Km value decreased with age and increased with fat free mass (FFM). INR prediction error (73.0%) of the external datasets was within ± 20%. CONCLUSION: A dose-response model of warfarin was established based on the relationship between daily warfarin dose and INR. Expected genotype effects on Km and demographic characteristics were confirmed. The model has the potential to be a powerful tool for individualized warfarin therapy for Chinese outpatients.
Entities:
Keywords:
Dose–response model; International normalized ratio; Pharmacogenomics; Warfarin