Original ArticlePopulation Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary SyndromeMomčilović, Stefan MD*; Milovanović, Jasmina R. MD, PhD†; Janković, Slobodan M. MD, PhD†; Jovanović, Andriana MD*,‡; Tasić-Otašević, Suzana MD, PhD*; Stanojević, Dragana MD, PhD§; Krstić, Miroslav MD§; Šalinger-Martinović, Sonja MD, PhD§,¶; Radojković, Danijela Djordjević MD, PhD§; Damjanović, Miodrag MD, PhD§; Živković, Milan MD§; Maričić, Bojan MD*; Ranković, Goran MD, PhD║; Mihajlović, Aleksandar MD§; Nikolić, Valentina N. MD, PhD**Author Information *Faculty of Medicine, University of Niš, Serbia; †Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Serbia; ‡Innovation center, University of Niš, Serbia; §Clinic for Cardiovascular Diseases, Clinical Center of Nš, Serbia; ¶Department of Cardiology, Faculty of Medicine, University of Nis, Serbia; ‖Department of Physiology, Faculty of Sports and Physical Education, University of Pristina, Serbia; and **Department of Pharmacology and Toxicology, Faculty of Medicine, University of Niš, Serbia. Reprints: Stefan Momčilović, MD, Faculty of Medicine, University of Niš, Serbia, Boulevard Zorana Djindjića 81, 18000 Niš, Serbia (e-mail: [email protected]). Supported by the Serbian Ministry of Education and Science grant No III41007, grant No 175007 and grant No 41018. The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: March 2019 - Volume 73 - Issue 3 - p 136-142 doi: 10.1097/FJC.0000000000000644 Buy Metrics 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. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.