Tags

Type your tag names separated by a space and hit enter

Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling.
Acta Pharmacol Sin. 2012 Nov; 33(11):1359-71.AP

Abstract

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, C(max), and T(max)) were reasonably consistent (<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.

Links

PMC Free PDF
PMC Free Full Text

Authors+Show Affiliations

Li GF
Center for Drug Clinical Research, Shanghai University of Chinese Medicine, China.
Wang K
No affiliation info available
Chen R
No affiliation info available
Zhao HR
No affiliation info available
Yang J
No affiliation info available
Zheng QS
No affiliation info available

MeSH

Administration, IntravenousAdministration, OralAdrenergic beta-1 Receptor AntagonistsAdultArea Under CurveBisoprololComputer SimulationDose-Response Relationship, DrugFemaleHumansMaleMiddle AgedModels, BiologicalMonte Carlo MethodRenal InsufficiencyTissue DistributionYoung Adult

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23085739

Citation

Li, Guo-fu, et al. "Simulation of the Pharmacokinetics of Bisoprolol in Healthy Adults and Patients With Impaired Renal Function Using Whole-body Physiologically Based Pharmacokinetic Modeling." Acta Pharmacologica Sinica, vol. 33, no. 11, 2012, pp. 1359-71.
Li GF, Wang K, Chen R, et al. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacol Sin. 2012;33(11):1359-71.
Li, G. F., Wang, K., Chen, R., Zhao, H. R., Yang, J., & Zheng, Q. S. (2012). Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacologica Sinica, 33(11), 1359-71. https://doi.org/10.1038/aps.2012.103
Li GF, et al. Simulation of the Pharmacokinetics of Bisoprolol in Healthy Adults and Patients With Impaired Renal Function Using Whole-body Physiologically Based Pharmacokinetic Modeling. Acta Pharmacol Sin. 2012;33(11):1359-71. PubMed PMID: 23085739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. AU - Li,Guo-fu, AU - Wang,Kun, AU - Chen,Rui, AU - Zhao,Hao-ru, AU - Yang,Jin, AU - Zheng,Qing-shan, Y1 - 2012/10/22/ PY - 2012/10/23/entrez PY - 2012/10/23/pubmed PY - 2013/11/8/medline SP - 1359 EP - 71 JF - Acta pharmacologica Sinica JO - Acta Pharmacol Sin VL - 33 IS - 11 N2 - 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, C(max), and T(max)) were reasonably consistent (<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. SN - 1745-7254 UR - https://www.unboundmedicine.com/medline/citation/23085739/Simulation_of_the_pharmacokinetics_of_bisoprolol_in_healthy_adults_and_patients_with_impaired_renal_function_using_whole_body_physiologically_based_pharmacokinetic_modeling_ L2 - https://doi.org/10.1038/aps.2012.103 DB - PRIME DP - Unbound Medicine ER -