Background
Metformin hydrochloride constitutes a cornerstone in the management of type 2 diabetes mellitus. However, MH exhibits a negative food effect that complicates its pharmacokinetic profile. This is particularly concerning in clinical settings, as patients are frequently advised to administer MH tablets concomitantly with food to mitigate GI adverse effects. Empirical evidence suggests that a high-calorie diet reduces the overall bioavailability of metformin. However, it remains unclear what exact factors influence these food-induced pharmacokinetic alterations. PBPK Modeling offers a robust mechanistic framework for predicting and elucidating the impact of food intake on the absorption kinetics of orally administered drugs.
Methods
A PBPK model for metformin was developed utilizing GastroPlus™ software version 9.8.3. Initially, an adult IV PBPK model was developed to derive non-compartmental analysis parameters. Then, an adult oral PBPK model was established with the addition of experimentally obtained dissolution data, permeability metrics, and population data from three study groups administered 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 mechanism involving OCT1, PMAT, and SERT transporters accompanied by a slowing of GI transit. Administration of a high-fat, high-calorie meal resulted in a 30% reduction in the Cmax and a three-hour delay in the Tmax compared to a low-fat, moderate-calorie meal. The interaction between bile acids and alterations in GI transporter kinetics were identified as the principal factors underlying this food effect on metformin pharmacokinetics.
Conclusion
The findings of this study present a comprehensive mechanistic model for the pharmacokinetic disposition of metformin and address significant deficiencies in diabetic treatment. Subsequent work will aim to incorporate formulation modifications as well as considerations for pregnant patients with gestational diabetes.
References
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- Sun, M. L., et al. (2023). “Effects of food on pharmacokinetics and safety of metformin hydrochloride tablets: A meta-analysis of pharmacokinetic, bioavailability, or bioequivalence studies.” Heliyon 9(7): e17906.
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