What affects the elimination of bisoprolol in diabetics and patients with acute coronary syndrome?
Beta-blockers are widely used to reduce cardiovascular (CV) risk in a number of diseases. However, information about the pharmacokinetics of these drugs is still far from complete. Two studies focused on the population pharmacokinetics (PopPK) of bisoprolol in patients with type 2 diabetes mellitus (DM2) and ischemic heart disease (IHD), and we summarize their conclusions.
Population Pharmacokinetics
PopPK studies the interindividual variability of drug plasma concentrations in specific patient populations and aims to uncover how patient characteristics such as age, renal function, disease stage, and others influence pharmacokinetic (PK) parameters. Information from these studies helps refine clinical recommendations for drug use in target populations.
PK Profile of Bisoprolol
Bisoprolol is a highly selective β1-receptor blocker that reduces heart rate, blood pressure, heart work, and myocardial oxygen consumption. It is a moderately lipophilic substance with a low binding to plasma proteins (30%) and a biological half-life of 10–11 hours. It is well absorbed after oral administration, with a bioavailability of 90% and a very low first-pass liver effect. Fifty percent of the administered dose is eliminated by the liver, and the other half is excreted by the kidneys.
Pharmacokinetics in DM2
The presence of diabetes can affect the absorption, distribution, metabolism, and excretion of numerous drugs. Therefore, it is crucial to specifically study the PK of drugs widely used in diabetic patients.
The study published in the European Journal of Clinical Pharmacology involved 70 adult patients (40 women and 30 men) with hypertension and DM2 who had been taking bisoprolol for more than 1 month. Patients with liver or renal insufficiency were excluded. Bisoprolol was taken 1–2 times daily in a total daily dose of 1.25–10 mg, and drug concentration was measured at the time of maximum plasma level (tmax), i.e., 2 hours after drug intake.
Measured plasma concentration values ranged from 1–103 ng/ml. From the measured values and patient characteristics, a PopPK model for bisoprolol clearance was created. A total of 21 parameters were examined that could influence the drug's clearance, but only creatinine clearance, reflecting renal function, showed significant influence. Although bisoprolol is also eliminated hepatically, this route is likely unable to fully compensate for reduced renal function. This may also be due to the lower activity of the CYP3A4 isoenzyme in diabetics, which normally metabolizes nearly one-third of the administered bisoprolol dose.
Pharmacokinetics in IHD
Bisoprolol is a common part of the therapy after an episode of acute coronary syndrome (ACS) due to its beneficial effects on ischemic myocardium. The second PopPK study focused precisely on this patient population.
These were patients with ischemic heart disease (IHD) who had been taking bisoprolol for more than 1 month before hospitalization for ACS. Patients with left ventricular ejection fraction (LVEF) < 40% or liver or renal insufficiency were excluded. A total of 71 adult patients (53 men and 18 women) participated in the study, receiving bisoprolol in a total daily dose of 0.625–7.5 mg, and plasma drug concentrations were measured 3 days after ACS again at tmax.
Plasma concentrations of bisoprolol ranged from 3.8–71.1 ng/ml. The PopPK model revealed that two factors significantly influenced bisoprolol clearance – daily dose and smoking. Drug clearance increased with higher daily doses, a phenomenon also observed in patients with heart failure for which there currently is no complete explanation. Conversely, the induction of biotransformation enzymes by cigarette smoke and the subsequent faster elimination of some drugs is a well-known effect.
Conclusion
In patients with diabetes and hypertension, creatinine clearance significantly affects the elimination of bisoprolol. Therefore, it is essential to routinely measure renal functions and adjust drug dosing individually based on these measurements. In patients after an ACS episode, daily dose and smoking influenced bisoprolol elimination. Given the potentially lower effect of bisoprolol in smokers, it may be beneficial to monitor their heart rate more frequently and again individually adjust dosing.
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Sources:
1. Momčilović S., Jovanović A., Radojković D. et al. Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension. Eur J Clin Pharmacol 2020; 76, 1539–1546, doi: 10.1007/s00228-020-02937-6.
2. Momčilović S., Milovanović J. R., Janković S. M. et al. Population pharmacokinetic analysis of bisoprolol in patients with acute coronary syndrome. J Cardiovasc Pharmacol 2019; 73 (3), 136–142, doi: 10.1097/FJC.0000000000000644.
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