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Clinical Pharmacokinetics

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01-02-2015 | Original Research Article

Prediction of Drug Disposition in Diabetic Patients by Means of a Physiologically Based Pharmacokinetic Model

Authors: Jia Li, Hai-fang Guo, Can Liu, Zeyu Zhong, Li Liu, Xiao-dong Liu

Published in: Clinical Pharmacokinetics | Issue 2/2015

Abstract

Background and Objective

Accumulating evidence has shown that diabetes mellitus may affect the pharmacokinetics of some drugs, leading to alteration of pharmacodynamics and/or toxic effects. The aim of this study was to develop a novel physiologically based pharmacokinetic (PBPK) model for predicting drug pharmacokinetics in patients with type 2 diabetes mellitus quantitatively.

Methods

Contributions of diabetes-induced alteration of physiological parameters including gastric emptying rates, intestinal transit time, drug metabolism in liver and kidney functions were incorporated into the model. Plasma concentration–time profiles and pharmacokinetic parameters of seven drugs (antipyrine, nisoldipine, repaglinide, glibenclamide, glimepiride, chlorzoxazone, and metformin) in non-diabetic and diabetic patients were predicted using the developed model. The PBPK model coupled with a Monte-Carlo simulation was also used to predict the means and variability of pharmacokinetic parameters.

Results

The predicted area under the plasma concentration–time curve (AUC) and maximum (peak) concentration (C _max) were reasonably consistent (<2-fold errors) with the reported values. Sensitivity analysis showed that gut transit time, hepatic enzyme activity, and renal function affected the pharmacokinetic characteristics of these drugs. Shortened gut transit time only decreased the AUC of controlled-released drugs and drugs with low absorption rates. Impairment of renal function markedly altered pharmacokinetics of drugs mainly eliminated via the kidneys.

Conclusion

All of these results indicate that the developed PBPK model can quantitatively predict pharmacokinetic alterations induced by diabetes.

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Title: Prediction of Drug Disposition in Diabetic Patients by Means of a Physiologically Based Pharmacokinetic Model
Authors: Jia Li
Hai-fang Guo
Can Liu
Zeyu Zhong
Li Liu
Xiao-dong Liu
Publication date: 01-02-2015
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 2/2015
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0192-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Prediction of Drug Disposition in Diabetic Patients by Means of a Physiologically Based Pharmacokinetic Model

Abstract

Background and Objective

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusion

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