Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension
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PHARMACOKINETICS AND DISPOSITION
Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension Stefan Momčilović 1 & Andriana Jovanović 1 & Danijela Radojković 2,3 & Valentina N. Nikolić 4 & Slobodan M. Janković 5 & Milica Pešić 2,3 & Jasmina R. Milovanović 5 Received: 2 September 2019 / Accepted: 16 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Given that it has been reported that type 2 diabetes mellitus may affect the pharmacokinetics of a large number of drugs and that there are still no published population pharmacokinetic (PopPK) analyses in routinely treated patients with hypertension and type 2 diabetes mellitus as comorbid condition, the aim of this study was to determine PK variability of bisoprolol in 70 Serbian patients using the PopPK approach. Methods PopPK analysis was conducted using a nonlinear mixed effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. The drug was administrated orally as a single daily dose or in two divided doses per day. Results A wide range of the drug concentrations were noted (1–103 ng/mL) in the population consisted of the adult patients with type 2 diabetes mellitus. From a total of 21 separately assessed covariates, our results indicated that only creatinine clearance could have a potential impact on the variability of the clearance of bisoprolol. Conclusion Routine assessment of renal function should be carried out before the initiation of treatment with bisoprolol in order to individualize the dose and to prevent possible accumulation and adverse drug reactions. Keywords Pharmacokinetics . HPLC . Drug analysis . Diabetes
1.Introduction Beta-adrenoceptor blockers, as a specific class of antihypertensive drugs, have been widely used to reduce cardiovascular Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-02937-6) contains supplementary material, which is available to authorized users. * Stefan Momčilović [email protected] 1
Faculty of Medicine, University of Niš, Blvd Zorana Djindjića 81, Niš 18000, Serbia
2
Department of Endocrinology, Faculty of Medicine, University of Niš, Niš, Serbia
3
Clinic for Endocrinology, Clinical Center of Niš, Niš, Serbia
4
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Niš, Niš, Serbia
5
Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
risk in patients with hypertension [1, 2]. These agents, by blocking the action of endogenous catecholamines on betaadrenergic receptors, decrease heart rate, reduce myocardial contractility, and suppress renin release, thus lowering the blood pressure [3]. Despite the fact that the use of βblockers as the first-line therapy for hypertension came under criticism since the 1990s, these agents are still preferred in hypertensive patients with other comorbidities such as ischemic heart
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