Abstract

Background: There is growing evidence that diabetes mellitus modifies the pharmacokinetics of several medications, changing their pharmacodynamics. To understand these changes, in this study, we develop a physiologically based pharmacokinetic (PBPK) model to predict drug disposition in diabetic patients.

Methods: The PBPK model coupled with the GastroPlusTM version 9.5 software (Simulation Plus Inc., Lancaster, CA) was utilized to predict the means and variability of pharmacokinetic parameters. A whole-body PBPK model with key diabetic-related physiological changes was developed, in order to characterize the pharmacokinetics of the tested drugs in diabetic patients and compare these parameters to those in healthy subjects. Data related to physiological and biological changes in diabetic patients were obtained from the literature and incorporated into a structural PBPK model describing the PK data of healthy subjects.

Results: Glibenclamide (mainly metabolized by CYP2C9) and chlorzoxazone (metabolized by CYP2E1 and CYP1A2) were used for model development and validation. Changes in glibenclamide and chlorzoxazone area under the curve (AUC) and maximum concentration (Cmax) values in diabetic patients were predicted. The simulated PK profiles were comparable with the observed values, with predicted-to-observed ratio in the range of 0.8–1.2.

Conclusion: In vitro data and information from a healthy population were successfully used to predict the pharmacokinetic profiles of medications in diabetic patients using the developed DM-PBPK model, which included changes in numerous anatomical, physiological, and biochemical characteristics caused by diabetes. When no clinical trials are available to guide dose recommendations in diabetic patients, the DM-PBPK model offers a workable substitute for empirical dosage selection.

By Saeed Alqahtani, Hajar Alsaleh & Abdullah Alsultan