Bisoprolol Consistently Shows Lower Pharmacokinetic Variability vis-à-vis Other Beta-blockers Used in Cardiology
Introduction
β-blockers are widely indicated in cardiology practice in the prevention and treatment of the commonest cardiovascular diseases, including heart failure, ischemic heart disease, hypertension, and arrhythmias. In these indications, the optimal use of β-blockers often results in functional improvements as well as reductions in morbidity and mortality.
However, the clinical effects of all β-blockers are not the same and significant intraclass variation has been reported for β-blockers. Additionally, significant interpatient variability in the clinical response has also been reported for some β-blockers. The intraclass and interpatient variability for β-blockers can be caused by many factors, such as the pharmacokinetic variability, pharmacodynamic variability, variability in disease expression, drug-drug interactions, and comorbidities.
Pharmacokinetic variability of β-blockers refers to the interindividual differences in their absorption, distribution, metabolism, and excretion (ADME). These differences in the ADME, such as in the intestinal permeability, protein binding, first-pass metabolism, hydrophilicity, and renal or hepatic excretion can account for a significantly varied interindividual clinical response, which is commonly observed in clinical practice.
Notably, an unfavorable pharmacokinetic profile of the β-blocker can increase the incidence of an insufficient response and adverse effects, and may even worsen the clinical outcomes. Conversely, a favorable pharmacokinetic profile of a β-blocker can help to reach the desired clinical response, minimize adverse effects, and even improve clinical outcomes. Therefore, a good understanding of the pharmacokinetic profile of β-blockers is required to optimize and personalize the use of β-blockers in the cardiac clinic.
Aims
This review of literature by Agesen et al.1 conducted pharmacokinetics comparisons for β-blockers indicated in cardiology. The review aimed to examine and analyze the pharmacokinetic variability of β-blockers in healthy volunteers and hypertensive individuals who participated in the individual pharmacokinetics-determining studies, in order to guide a safe and personalized use of β-blockers in the cardiac clinic.
Methods
The authors conducted a literature search on PubMed in June 2018 and included published original studies reporting the pharmacokinetics of 14 β-blockers indicated in cardiology practice. The β-blockers included in the review were atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, sotalol, and timolol. The inclusion of these β-blockers in the study was based on meeting the essential requirements of demonstration of superiority to placebo in at least 2 randomized clinical trials.
However, studies reporting the pharmacokinetics of only oral doses of β-blockers, both single doses as well as multiple doses (steady-state studies), in healthy volunteers were included in this review. Additionally, the studies with subjects having hypertension but normal renal and hepatic function were also included, while those with subjects receiving concomitant medications were excluded. However, studies with insufficient data for calculation of coefficient of variation (CV) were excluded.
The pharmacokinetic variability was determined by two ways: CV for the maximum plasma concentration (Cmax), and the area under the concentration curve (AUC). The following formula was used to calculate CV for individual studies: CV = SD/mean. The CV for each study was classified as follows: <20%, 20%‐40%, 40%‐60%, 60%‐80%, or > 80%, which was then regrouped into 2 categories: high (CV > 40%) and low or moderate (CV < 40%) variability.
Summary of Key Results
This review included 192 pharmacokinetic publications on 13 β-blockers (not 14, because there were no data available for oral administration of esmolol) that are used in clinical cardiology. In these 192 publications, the Cmax was reported in 225 single‐dose and 101 multiple‐dose studies, while the AUC was reported in 233 single‐dose and 113 multiple‐dose studies.
The cloud plot of the distribution of the CV in β-blockers for the AUC in multiple-dose and single‐dose studies is shown in Figure 1. As can be noted from Figure 1, Metoprolol showed remarkably high pharmacokinetic variability followed by that of Nebivolol, and Carvedilol. In contrast, Bisoprolol was consistently shown to possess the least pharmacokinetic variability and none of the study on bisoprolol showed a high pharmacokinetic variability with CV of over 40%.
(Figure 1).
Figure 1. Cloud Plot of the distribution of pharmacokinetic variability in steady-state (SS) and single-dose (SD) studies
Discussion and Conclusion
In this review, the authors revealed the comparative pharmacokinetic variability of β-blockers. Their findings can be immensely helpful in guiding the choice of β-blocker and personalizing the β-blocker selection in clinical cardiology, since the optimal β‐blocker can lower the risk of myocardial infarction and sudden cardiac death and minimize the number of adverse events. Since there is not much difference in the clinical efficacy of β-blockers in cardiological indications, the choice of β-blocker can thus be guided by pharmacokinetic considerations.
In this analysis, Metoprolol, Carvedilol, and Nebivolol showed very high pharmacokinetic variability among the 13 studied β-blockers, conversely Bisoprolol consistently showed low pharmacokinetic variability. This differential variability can be explained by the pharmacokinetic properties, particularly the lipid solubility, and hepatic metabolism or elimination, as shown in Figure 2. As it can be interpreted from Figure 2, Bisoprolol consistently outperforms all other β-blockers in terms of all pharmacokinetic parameters, including extent of absorption, bioavailability, first-pass metabolism, and lipid solubility, which can explain its predictable pharmacokinetic profile. Therefore, the authors suggested that β‐blockers with high pharmacokinetic variability should be more cautiously initiated in cardiological indications, and their daily maintenance doses may vary between patients.
Figure 2. Pharmacokinetic properties of beta-blockers
In conclusion, the authors revealed marked variation in pharmacokinetic variability of different β‐blockers ranging between low (bisoprolol) to high (metoprolol). By combining these findings with the individual patient’s characteristics, a more personalized treatment may be obtained that can help in minimizing the occurrence of adverse events or a lack of clinical effect.
Reference
1. Ågesen FN, Weeke PE, Tfelt-Hansen P, Tfelt-Hansen J; for ESCAPE‐NET. Pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology. Pharmacol Res Perspect. 2019;7(4):e00496. Published 2019 Jul 12. doi:10.1002/prp2.496
CODE : IN-CONCO-00008
