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Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations

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Abstract

Background

Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown.

Methods

Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients.

Results

Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 μg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 −1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4.

Conclusions

Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

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Acknowledgements

The authors are grateful to Naoko Kaneko for her technical assistance.

Author information

Author notes

  1. Minami Ohara and Yasuhiko Suzuki contributed equally to this work.

Authors and Affiliations

  1. Department of Biopharmaceutics, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose, Tokyo, 204-8588, Japan

    Minami Ohara, Yasuhiko Suzuki, Saki Shinohara & Harumi Takahashi

  2. Division of Clinical Pharmacology, University of Western Ontario, London, ON, Canada

    Inna Y. Gong, Crystal L. Schmerk, Rommel G. Tirona, Ute I. Schwarz & Richard B. Kim

  3. Department of Internal Medicine, Linkou and Chang Gung University College of Medicine, Tauyuan, Taiwan

    Ming-Shien Wen

  4. Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA

    Ming Ta Michael Lee

  5. Faculty of Pharmacy, Center for Clinical Pharmacy, Musashino University, Tokyo, Japan

    Kiyoshi Mihara

  6. Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA

    Edith A. Nutescu

  7. Department of Pharmacology, Northwestern University, Chicago, IL, USA

    Minoli A. Perera

  8. Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA

    Larisa H. Cavallari

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  1. Minami Ohara
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Contributions

HT, RBK, MTML, MAP, KM, and LHC designed the study and revised the manuscript. MO, YS, SS, IYG, CS, RGT, UIS, EAN, and MSW performed the research and conducted the PK and PD analyses. HT and MO wrote the manuscript.

Corresponding author

Correspondence to Harumi Takahashi.

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Conflict of interest

Minami Ohara, Yasuhiko Suzuki, Saki Shinohara, Inna Y. Gong, Crystal L. Schmerk, Rommel G. Tirona, Ute I. Schwarz, Ming-Shien Wen, Ming Ta Michael Lee, Kiyoshi Mihara, Edith A. Nutescu, Minoli A. Perera, Larisa H. Cavallari, Richard B. Kim and Harumi Takahashi declare that they have no conflicts of interest.

Funding

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI C, 20590548), the Department of Health, Taiwan (DOH101-TD-PB-111-TM005), an American Heart Association Midwest Affiliate Spring 2010 Grant-in-Aid (10GRNT3750024) and the Drug Innovation Fund established by the Ministry of Health and Long-Term Care, Canada.

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Ohara, M., Suzuki, Y., Shinohara, S. et al. Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations. Clin Pharmacokinet 58, 1077–1089 (2019). https://doi.org/10.1007/s40262-019-00745-5

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