Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms

K. Kubo; M. Ohara; M. Tachikawa; L. H. Cavallari; M. T M Lee; M. S. Wen; M. G. Scordo; E. A. Nutescu; M. A. Perera; A. Miyajima; N. Kaneko; V. Pengo; R. Padrini; Y. T. Chen; H. Takahashi

doi:10.1038/tpj.2016.57

Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms

K. Kubo, M. Ohara, M. Tachikawa, L. H. Cavallari, M. T M Lee, M. S. Wen, M. G. Scordo, E. A. Nutescu, M. A. Perera, A. Miyajima, N. Kaneko, V. Pengo, R. Padrini, Y. T. Chen, H. Takahashi^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9∗2,∗3 and ∗8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h^-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9∗1/∗1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.

Original language	English (US)
Pages (from-to)	494-500
Number of pages	7
Journal	Pharmacogenomics Journal
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/tpj.2016.57
State	Published - Dec 1 2017

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), and an American Heart Association Midwest Affiliate Spring 2010 Grant-in Aid (10GRNT3750024).

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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10.1038/tpj.2016.57

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Kubo, K., Ohara, M., Tachikawa, M., Cavallari, L. H., Lee, M. T. M., Wen, M. S., Scordo, M. G., Nutescu, E. A., Perera, M. A., Miyajima, A., Kaneko, N., Pengo, V., Padrini, R., Chen, Y. T., & Takahashi, H. (2017). Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms. Pharmacogenomics Journal, 17(6), 494-500. https://doi.org/10.1038/tpj.2016.57

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title = "Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms",

abstract = "Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9∗2,∗3 and ∗8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9∗1/∗1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.",

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Kubo, K, Ohara, M, Tachikawa, M, Cavallari, LH, Lee, MTM, Wen, MS, Scordo, MG, Nutescu, EA, Perera, MA, Miyajima, A, Kaneko, N, Pengo, V, Padrini, R, Chen, YT & Takahashi, H 2017, 'Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms', Pharmacogenomics Journal, vol. 17, no. 6, pp. 494-500. https://doi.org/10.1038/tpj.2016.57

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AU - Kubo, K.

AU - Ohara, M.

AU - Tachikawa, M.

AU - Cavallari, L. H.

AU - Lee, M. T M

AU - Wen, M. S.

AU - Scordo, M. G.

AU - Nutescu, E. A.

AU - Perera, M. A.

AU - Miyajima, A.

AU - Kaneko, N.

AU - Pengo, V.

AU - Padrini, R.

AU - Chen, Y. T.

AU - Takahashi, H.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9∗2,∗3 and ∗8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9∗1/∗1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.

AB - Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9∗2,∗3 and ∗8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9∗1/∗1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.

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Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: Their influence on pharmacogenetic dosing algorithms

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