<i>CYP2D6</i> polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta‐analysis

Meloche, Maxime; Khazaka, Michael; Kassem, Imad; Barhdadi, Amina; Dubé, Marie‐Pierre; Denus, Simon de

doi:10.1111/bcp.14247

Cited by 40 publications

(27 citation statements)

References 51 publications

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“…Due to the cross‐sectional nature of this analysis, it does not in fact reflect “response” to metoprolol. Thus, despite this observation in previous smaller prospective studies, 33 bias and chance cannot be excluded. Given the association between higher heart rate and worse outcomes in cardiovascular disease, 34 studies investigating the impact of CYP2D6 metabolizer status on the clinical outcomes of patients undergoing metoprolol therapy appear warranted.…”

Section: Discussionmentioning

confidence: 58%

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

Meloche

Leclair

Jutras

et al. 2022

Clinical Translational Sci

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Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease‐related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross‐sectional, proof‐of‐concept association study to replicate the well‐established association between metoprolol concentrations and CYP2D6 genotype‐inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α‐hydroxymetoprolol (α‐OH‐metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6‐inferred phenotype was significantly associated with both metoprolol and α‐OH‐metoprolol in unadjusted and adjusted models (all p < 10 −14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

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Section: Discussionmentioning

confidence: 58%

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

Meloche

Leclair

Jutras

et al. 2022

Clinical Translational Sci

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“…The effect of CYP2D6 genotype on the hemodynamic and clinical responses to metoprolol has not been consistent but a meta-analysis of seven studies in 2017 concluded that CYP2D6 polymorphisms significantly influenced the heart rate (HR) and diastolic blood pressure (DBP), but not the systolic blood pressure (SBP) response to metoprolol ( 9 ). A more recent meta-analysis of 15 studies found that CYP2D6 poor metabolizers (PM) had significantly greater reductions in HR, SBP and DBP compared to non-PM individuals ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP2D6 and CYP3A5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Bisoprolol in Hypertensive Chinese Patients

Chan

Chu

et al. 2021

Front. Med.

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Purpose: This study was performed to investigate the effects of common polymorphisms in CYP2D6 and CYP3A5 on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients.Methods: One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism were genotyped by TaqMan® assay.Results: After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg (P < 0.01) and 6.3 ± 7.6 BPM (P < 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight (P < 0.001) but there was no significant effect of the CYP2D6 and CYP3A5 polymorphisms on these or the trough plasma concentrations. There was no significant association of the CYP2D6 and CYP3A5 polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol.Conclusion: Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in CYP2D6 that were examined and the CYP3A5*3 polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.

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“…Next, UMs appear to have a better safety profile. Compared with individuals with other metabolic phenotypes, UMs have significantly higher CYP2D6 enzyme activity ( Blake et al, 2013 ; Meloche et al, 2020 ). After metoprolol intake, UMs have high drug clearance and low plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

Impact of the CYP2D6 Genotype on Metoprolol Tolerance and Adverse Events in Elderly Chinese Patients With Cardiovascular Diseases

et al. 2022

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The latest consensus has changed CYP2D6 genotyping among Chinese population, while its impact on metoprolol tolerance and adverse events in elderly Chinese patients with cardiovascular diseases remains unclear. In this study, we prospectively included elderly patients who started metoprolol treatment for cardiovascular indications. According to the latest consensus on CYP2D6 genotype-to-phenotype translation, the patients were categorized as normal, intermediate, or poor metabolizers (NMs, IMs, or PMs, respectively) by detecting the presence of the CYP2D6*1, *2, *5, *10, and *14. Logistic regression model was used to analyze the correlation between the CYP2D6 phenotype and incidence of adverse events, which were assessed over a 12-week period. In this study, there were 651 (62.7%) NMs, 385 (37.1%) IMs, and 3 (0.3%) PMs. After 12 weeks of follow-up, compared with NMs, IMs had the lower maintenance dose [50.0 (25.0–50.0) mg/day vs. 25.0 (25.0–50.0) mg/day, p < 0.001] and lower weight-adjusted maintenance doses (0.52 ± 0.25 mg/day/kg vs. 0.42 ± 0.22 mg/day/kg, p < 0.001), and had higher incidence of postural hypotension (6.0% vs. 10.9%, p = 0.006), bradycardia (21.5% vs. 28.6%, p = 0.011), asystole (0.8% vs. 3.1%, p = 0.009) and syncope (2.0% vs. 6.2%, p = 0.001). In logistic regression model, the overall incidence of adverse events was 1.37-fold larger in IMs than in NMs (odds ratio = 1.37, 95% confidence interval = 1.05–1.79, p = 0.021). We conclude that IMs have lower tolerance and higher incidence of metoprolol-related adverse events than NMs in elderly Chinese patients with cardiovascular diseases. CYP2D6 genotyping is justifiable in elderly patients to minimize the risk of adverse events and ensure the benefits of metoprolol.

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CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta‐analysis

Cited by 40 publications

References 51 publications

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

Influence of CYP2D6 and CYP3A5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Bisoprolol in Hypertensive Chinese Patients

Impact of the CYP2D6 Genotype on Metoprolol Tolerance and Adverse Events in Elderly Chinese Patients With Cardiovascular Diseases

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