Abstract
Vildagliptin (VDG) is a dipeptidyl-peptidase-4 (DPP-4) inhibitor used for type 2 diabetes (T2DM) treatment. Viewing to improve VDG treatment, a population pharmacokinetic (popPK) model was built to describe drug plasma, free liver and muscle concentrations determined by microdialysis in healthy and diabetic animals following 50 mg/kg i.v. bolus administration. A four-compartment popPK model with linear elimination and bidirectional transport between tissues and the central compartment described the data with diabetes as a covariate in Q(1) and Q(out,liver). The pharmacokinetic parameters of VDG were scaled to humans using allometry, and used to simulate VDG tissue concentrations in patients with T2DM and relate them with the DPP-4 inhibition by an I(max) model. The efficacy of VDG was evaluated considering 80% and 92% DP-IV inhibition during the entire dosing interval. VDG 100 mg q24 h achieved 80% DPP-4 inhibition in plasma, but not in tissues. Although q12 h dosing interval reached 80% enzyme inhibition in plasma for > 25 mg doses, only the 100 mg reached this goal in muscle. The 92% enzyme inhibition was achieved in plasma for 50 and 100 mg q12 h but none of the dose regimens investigated reached this inhibition in tissues.