Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects*

ABSTRACT

Background: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simvastatin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. Therefore, this study was conducted to determine the potential for pharmacokinetic drug–drug interaction between vildagliptin and simvastatin at steady-state.

Methods: An open label, single center, multiple dose, three period, crossover study was conducted in 24?healthy subjects. All subjects received once daily doses of either vildagliptin 100?mg or simvastatin 80?mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin β-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively.

Results: The 90% confidence intervals of C_max and AUC_τ of vildagliptin, simvastatin, and simvastatin β-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were administered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study.

Conclusions: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.