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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 8/2019

01-08-2019 | Pharmacokinetics | Original Research Article

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

Authors: 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, Harumi Takahashi

Published in: Clinical Pharmacokinetics | Issue 8/2019

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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.
Appendix
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Metadata
Title
Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations
Authors
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
Harumi Takahashi
Publication date
01-08-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 8/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00745-5

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