Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

Aim： To develop and evaluate a whole-body physiologically based pharmacokinetic （WB-PBPK） model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. Methods： Bisoprolol dispositions in 14 tissue compartments were described by perfu...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2012-11, Vol.33 (11), p.1359-1371
Main Authors: Li, Guo-fu, Wang, Kun, Chen, Rui, Zhao, Hao-ru, Yang, Jin, Zheng, Qing-shan
Format: Article
Language:English
Subjects:
Administration, Intravenous
Administration, Oral
Adrenergic beta-1 Receptor Antagonists - administration & dosage
Adrenergic beta-1 Receptor Antagonists - pharmacokinetics
Adult
Area Under Curve
Bisoprolol - administration & dosage
Bisoprolol - pharmacokinetics
Computer Simulation
Dose-Response Relationship, Drug
Female
Humans
Male
Middle Aged
Models, Biological
Monte Carlo Method
Original
Renal Insufficiency - physiopathology
Tissue Distribution
Young Adult
健康
动力学建模
动力学模拟
患者
正常成人
比索洛尔
生理基础
肾功能损害
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Summary:Aim： To develop and evaluate a whole-body physiologically based pharmacokinetic （WB-PBPK） model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. Methods： Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the ＇Advanced Compartmental Absorption Transit＇ （ACAT） model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. Results： The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters （AUC, Cmax, and Tmax） were reasonably consis- tent （〈1.3-fold error） with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. Conclusion： The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2012.103