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Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762806/ https://www.ncbi.nlm.nih.gov/pubmed/33067866 http://dx.doi.org/10.1002/psp4.12563 |
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author | Thomas, Cameron D. Mosley, Scott A. Kim, Sarah Lingineni, Karthik El Rouby, Nihal Langaee, Taimour Y. Gong, Yan Wang, Danxin Schmidt, Siegfried O. Binkley, Philip F. Estores, David S. Feng, Kairui Kim, Hyewon Kinjo, Minori Li, Zhichuan Fang, Lanyan Chapman, Arlene B. Cooper-DeHoff, Rhonda M. Gums, John G. Hamadeh, Issam S. Zhao, Liang Schmidt, Stephan Frye, Reginald F. Johnson, Julie A. Cavallari, Larisa H. |
author_facet | Thomas, Cameron D. Mosley, Scott A. Kim, Sarah Lingineni, Karthik El Rouby, Nihal Langaee, Taimour Y. Gong, Yan Wang, Danxin Schmidt, Siegfried O. Binkley, Philip F. Estores, David S. Feng, Kairui Kim, Hyewon Kinjo, Minori Li, Zhichuan Fang, Lanyan Chapman, Arlene B. Cooper-DeHoff, Rhonda M. Gums, John G. Hamadeh, Issam S. Zhao, Liang Schmidt, Stephan Frye, Reginald F. Johnson, Julie A. Cavallari, Larisa H. |
author_sort | Thomas, Cameron D. |
collection | PubMed |
description | Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S‐metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2–2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25–1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25–1.5 vs. 2–2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (−10.8 ± 5.5) vs. 2–2.25 (−7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25–1.5 (−9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice. |
format | Online Article Text |
id | pubmed-7762806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77628062020-12-28 Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores Thomas, Cameron D. Mosley, Scott A. Kim, Sarah Lingineni, Karthik El Rouby, Nihal Langaee, Taimour Y. Gong, Yan Wang, Danxin Schmidt, Siegfried O. Binkley, Philip F. Estores, David S. Feng, Kairui Kim, Hyewon Kinjo, Minori Li, Zhichuan Fang, Lanyan Chapman, Arlene B. Cooper-DeHoff, Rhonda M. Gums, John G. Hamadeh, Issam S. Zhao, Liang Schmidt, Stephan Frye, Reginald F. Johnson, Julie A. Cavallari, Larisa H. CPT Pharmacometrics Syst Pharmacol Research Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S‐metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2–2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25–1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25–1.5 vs. 2–2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (−10.8 ± 5.5) vs. 2–2.25 (−7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25–1.5 (−9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice. John Wiley and Sons Inc. 2020-11-03 2020-12 /pmc/articles/PMC7762806/ /pubmed/33067866 http://dx.doi.org/10.1002/psp4.12563 Text en © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Thomas, Cameron D. Mosley, Scott A. Kim, Sarah Lingineni, Karthik El Rouby, Nihal Langaee, Taimour Y. Gong, Yan Wang, Danxin Schmidt, Siegfried O. Binkley, Philip F. Estores, David S. Feng, Kairui Kim, Hyewon Kinjo, Minori Li, Zhichuan Fang, Lanyan Chapman, Arlene B. Cooper-DeHoff, Rhonda M. Gums, John G. Hamadeh, Issam S. Zhao, Liang Schmidt, Stephan Frye, Reginald F. Johnson, Julie A. Cavallari, Larisa H. Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title | Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title_full | Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title_fullStr | Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title_full_unstemmed | Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title_short | Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores |
title_sort | examination of metoprolol pharmacokinetics and pharmacodynamics across cyp2d6 genotype‐derived activity scores |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762806/ https://www.ncbi.nlm.nih.gov/pubmed/33067866 http://dx.doi.org/10.1002/psp4.12563 |
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