Preclinical Modeling and Simulation to Explore the Tissue/Plasma Exposure and Pharmacodynamic Effect of Vildagliptin...

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 Q₁ 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.