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Genetic and pharmacological relationship between P-glycoprotein and increased cardiovascular risk associated with clarithromycin prescription: An epidemiological and genomic population-based cohort study in Scotland, UK

PLoS medicine, 2020-11, Vol.17 (11), p.e1003372 [Peer Reviewed Journal]

COPYRIGHT 2020 Public Library of Science ;COPYRIGHT 2020 Public Library of Science ;2020 Mordi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;2020 Mordi et al 2020 Mordi et al ;ISSN: 1549-1676 ;ISSN: 1549-1277 ;EISSN: 1549-1676 ;DOI: 10.1371/journal.pmed.1003372 ;PMID: 33226983

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Title:
Genetic and pharmacological relationship between P-glycoprotein and increased cardiovascular risk associated with clarithromycin prescription: An epidemiological and genomic population-based cohort study in Scotland, UK
Author: Mordi, Ify R ; Chan, Benjamin K ; Yanez, N David ; Palmer, Colin N A ; Lang, Chim C ; Chalmers, James D
Basu, Sanjay
Subjects: Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amoxicillin ; Analysis ; Anti-Bacterial Agents - adverse effects ; Anti-Bacterial Agents - therapeutic use ; Antibiotics ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - adverse effects ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; Biology and Life Sciences ; Cardiovascular disease ; Cardiovascular diseases ; Cardiovascular Diseases - chemically induced ; Cardiovascular Diseases - drug therapy ; Cardiovascular Diseases - genetics ; Chronic obstructive pulmonary disease ; Clarithromycin ; Clarithromycin - adverse effects ; Clarithromycin - therapeutic use ; Clinical pharmacology ; Cohort analysis ; Cohort Studies ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - chemically induced ; Diabetes Mellitus, Type 2 - complications ; Dosage and administration ; Drug therapy ; Engineering and Technology ; Epidemiology ; FDA approval ; Female ; Genomics ; Genotype & phenotype ; Glycoproteins ; Heart attacks ; Heart Disease Risk Factors ; Heterozygotes ; Hospitalization ; Humans ; Hypotheses ; Lung diseases ; Male ; Medicine and Health Sciences ; Methods ; Middle Aged ; Mortality ; Myocardial infarction ; Observational studies ; Obstructive lung disease ; P-Glycoprotein ; Patient outcomes ; Patients ; Pharmacogenomics ; Physiological aspects ; Population studies ; Prescriptions ; Prescriptions - statistics & numerical data ; Research and Analysis Methods ; Risk factors ; Scotland ; Single-nucleotide polymorphism ; Statistical analysis ; Young Adult
Is Part Of: PLoS medicine, 2020-11, Vol.17 (11), p.e1003372
Description: There are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug-drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism. We conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 -AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0-14 days, 15-30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0-14 days (HR 1.31; 95% CI 1.17-1.46, p < 0.001) and 30 days to 1 year (HR 1.13; 95% CI 1.06-1.19, p < 0.001), with the association at 0-14 days modified by use of P-gp inhibitors or substrates (interaction p-value: 0.029). In the pharmacogenomic study (13,544 individuals with 44,618 discrete prescribing episodes [37,497 amoxicillin, mean age 63 years, 56% male; 7,121 clarithromycin, mean age 66 years, 47% male]), when prescribed clarithromycin, individuals with genetically determined lower P-gp activity had a significantly increased risk of CV hospitalization at 30 days to 1 year compared with heterozygotes or those homozygous for the non-P-gp-lowering allele (rs1045642 AA: HR 1.39, 95% CI 1.20-1.60, p < 0.001, GG/GA: HR 0.99, 95% CI 0.89-1.10, p = 0.85, interaction p-value < 0.001 and rs1128503 AA 1.41, 95% CI 1.18-1.70, p < 0.001, GG/GA: HR 1.04, 95% CI 0.95-1.14, p = 0.43, interaction p-value < 0.001). The main limitation of our study is its observational nature, meaning that we are unable to definitively determine causality. In this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein.
Publisher: United States: Public Library of Science
Language: English
Identifier: ISSN: 1549-1676
ISSN: 1549-1277
EISSN: 1549-1676
DOI: 10.1371/journal.pmed.1003372
PMID: 33226983
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
Public Library of Science (PLoS)
ProQuest Central
DOAJ Directory of Open Access Journals

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Genetic and pharmacological relationship between P-glycoprotein and increased cardiovascular risk associated with clarithromycin prescription: An epidemiological and genomic population-based cohort study in Scotland, UK

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