Pharmacogenetic information in Swiss drug labels – a systematic analysis

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Abstract

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% ( n = 93) were classified as “actionable PGx”. Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group “nervous system”. Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

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Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s. Copyright © 2013 Elsevier Inc. All rights reserved.

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To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Prospective observational study. Two large general hospitals in Merseyside, England. 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is 466m pounds sterling (706m Euros, 847m dollars). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.

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Author and article information

Contributors

C. Jeiziner:

ORCID: http://orcid.org/0000-0002-1132-0240

chiara.jeiziner@unibas.ch

Journal

Journal ID (nlm-ta): Pharmacogenomics J

Journal ID (iso-abbrev): Pharmacogenomics J

Title: The Pharmacogenomics Journal

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1470-269X

ISSN (Electronic): 1473-1150

Publication date (Electronic): 17 October 2020

Publication date PMC-release: 17 October 2020

Publication date (Print): 2021

Volume: 21

Issue: 4

Pages: 423-434

Affiliations

[1 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Pharmaceutical Care Research Group, Department of Pharmaceutical Sciences, , University of Basel, ; Basel, 4001 Switzerland

[2 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, European Center of Pharmaceutical Medicine, Faculty of Medicine, , University of Basel, ; Basel, 4056 Switzerland

[3 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Biomedical Data Sciences, , Stanford University, ; Stanford, CA 94305 USA

[4 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Medicine, , Stanford University, ; Stanford, CA 94305 USA

[5 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Biopharmacy, Department of Pharmaceutical Sciences, , University of Basel, ; Basel, 4056 Switzerland

Author information

C. Jeiziner http://orcid.org/0000-0002-1132-0240

Article

Publisher ID: 195

DOI: 10.1038/s41397-020-00195-4

PMC ID: 8292148

PubMed ID: 33070160

SO-VID: 64575ec0-cf03-4779-bfa0-ca35d174a197

License:

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