Physiologically based pharmacokinetics model to assess the effect of food on absorption pharmacokinetics of metformin in adult type ii diabetic patients

Abstract

ABSTRACT Background: Metformin, a biguanide-class oral hypoglycemic medication, has formed the cornerstone in the management of type 2 diabetes. However, MH exhibits a negative food effect that complicates its pharmacokinetics. This is concerning because, in clinical practice, patients taking metformin are usually advised to take the medication with food to alleviate GI symptoms. Available data indicate that a High-calorie diet lowered the overall absorption rate of metformin, with a profound decrease in Cmax, and a delayed Tmax. However, whether these food effects were related to drug dosages, formulations, or patient factors remains unanswered. PBPK modeling is a powerful bottom-up approach that can be used to predict and explain how food intake affects the absorption of oral medication. Methods: A PBPK model for metformin was developed utilizing GastroPlus™ software version 9.8.3. Initially, an absorption PBPK model was established by incorporating experimentally obtained dissolution data, permeability metrics, and population data from three study groups that received varying doses of 250 mg, 500 mg, and 850 mg. This oral model was subsequently validated to assess its predictive accuracy against different pharmacokinetic datasets. The validated model was applied to simulate different fed states, evaluating the impact of both high- and low-calorie diets under these conditions. Results: The absorption PBPK model accurately predicted metformin’s low bioavailability and indicated that absorption primarily occurs through the paracellular pathway, with an additional contribution from an active, saturable transcellular movement. Administration of a high-fat, high-calorie meal resulted in more than 30% reduction in the Cmax but without a significant change in AUC (12%) and a 1.5-hour delay in the Tmax compared to the fasted state. Conclusion: The findings of this study present a comprehensive mechanistic model for the pharmacokinetic absorption of metformin in the presence of food