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Relationship between warfarin dosage and international normalized ratio: a dose–response analysis and evaluation based on multicenter data

  • Pharmacodynamics
  • Published:
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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.

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Acknowledgments

The authors would like to acknowledge the Chinese individualized drug therapy group of the International Network for the Rational Use of Drugs (INRUD). The authors would also like to acknowledge the English language editing of American Journal Experts.

Funding

This study was supported by the National Natural Science Foundation of China (grant numbers 81803628, 81700298, and 81503140), the National Key New Drug Creation Special Programs (2017ZX09304-021), the Suzhou Key Laboratory of Drug Clinical Research and Personalized Medicine (SZS201719), and People’s Livelihood Science and Technology Foundation of Suzhou Science and Technology Bureau (SYS201736).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China

    Ling Xue, Cheng Xie, Ling Zhou, Linsheng Liu & Liyan Miao

  2. Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China

    Yuzhen Zhang

  3. Department of Pharmacy, the Affiliated Wujin Hospital of Jiangsu University, Changzhou, China

    Haiyan Zhang

  4. Department of Clinical Laboratory, the Affiliated Wujin Hospital of Jiangsu University, Changzhou, China

    Lianhong Xu

  5. Department of pharmacy, Fuzhou General Hospital, Fuzhou, China

    Hongtao Song & Meiqin Lin

  6. Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China

    Hanfan Qiu

  7. Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China

    Junrong Zhu, Yubing Zhu & Jianjun Zou

  8. Department of Laboratory Medicine, East hospital of Yangpu district, Shanghai, China

    Wenfang Zhuang & Yingchao Fan

  9. Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, China

    Binbin Xuan & Yanhong Chen

  10. Department of Clinical Pharmacy, the First Affiliated Hospital of Kunming Medical University, Kunming, China

    Di Wu

  11. Department of Cardiovascular Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China

    Zhenya Shen

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  1. Ling Xue
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  4. Ling Zhou
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  15. Binbin Xuan
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  16. Yanhong Chen
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  17. Yingchao Fan
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  18. Di Wu
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  19. Zhenya Shen
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  20. Liyan Miao
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Corresponding authors

Correspondence to Zhenya Shen or Liyan Miao.

Ethics declarations

The present study was approved by the Health Authority Ethics Committee of the First Affiliated Hospital of Soochow University and was in accordance with the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no conflict of interest.

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Ling Xue, Yuzhen Zhang, and Cheng Xie should be considered joint first author.

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Xue, L., Zhang, Y., Xie, C. et al. Relationship between warfarin dosage and international normalized ratio: a dose–response analysis and evaluation based on multicenter data. Eur J Clin Pharmacol 75, 785–794 (2019). https://doi.org/10.1007/s00228-019-02655-8

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  • DOI: https://doi.org/10.1007/s00228-019-02655-8

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