Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome

Abstract

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed β1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625–7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Bisoprolol, Known to Be a Selective β1-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons

“…Clinically relevant serum concentration of BIS was recently reported to range between 3.8 and 71.1 ng/mL (or 0.011 and 0.22 µM) [46]. These values are similar to the IC 50 required for its suppression of I K(M) presented herein.…”

Association Between Use of Pharmacokinetic‐Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case‐Control Study

“…Bisoprolol does not show on the lists as P-gp or CYP3A4 inhibitor but is known to be metabolized partly by CYP3A4 (and partly by CYP2D6). [57][58][59][60] The specific interactions of dabigatran with verapamil, and rivaroxaban with verapamil or amiodarone, are consistent with previous reports in animal models 61 and in humans. 46,[62][63][64][65] Verapamil increased dabigatran exposure in real life.…”

“…Amiodarone exact strength of inhibition is still "yet to‐be‐determined" in the published lists 14 . Bisporolol, is known to be metabolized partly by CYP3A4 (and partly by CYP2D6) 57–60 . Amlodipine had been shown to affect P‐gp mediated transport, and is not a CYP3A4 inhibitor 31,32 …”

“…Bisoprolol, a beta‐receptor blocker, used by ~ 50% of patients in our AF cohort, was not previously associated with bleeding risk. Bisoprolol does not show on the lists as P‐gp or CYP3A4 inhibitor but is known to be metabolized partly by CYP3A4 (and partly by CYP2D6) 57–60 …”

Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol

“…Interestingly, a previous study has shown that smoking has a significant effect on bisoprolol clearance, possibly due to induction of CYP3A4. 23 Women have higher drug exposure and lower clearance of metoprolol, 24 but the influence of sex in the pharmacokinetics of bisoprolol has not been studied. The typical clearance estimated in our population was 13.1 L/h.…”