A whole-body physiologically based pharmacokinetic model of metformin, the fourth most commonly prescribed drug in the USA, has been carefully developed and evaluated to describe the metformin concentrations in blood, kidney, and urine. In addition, a whole-body physiologically based pharmacokinetic model of cimetidine, a potent multidrug and toxin extrusion protein 1 inhibitor used in drug–drug interaction studies, has been established.

These models have been applied to describe and predict the metformin-SLC22A2 808G>T drug–gene interaction, the cimetidine-metformin drug–drug interaction, and a combined drug–drug–gene interaction study, in which different SLC22A2 genotypes were additionally challenged with cimetidine co-administration.

Furthermore, the pathophysiological changes during renal impairment have been assessed and implemented to describe the increased metformin exposure of patients with different stages of chronic kidney disease. For severe chronic kidney disease, this analysis indicates an induction of organic cation transporter 2 and multidrug and toxin extrusion protein 1, possibly as an adaptation to progressing uremia/hyperuricemia. The final pathophysiologically based pharmacokinetic model was applied to generate metformin dosing recommendations for CKD3A-4 patients.