The Absolute Oral Bioavailability and??Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers

Abstract

Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers. This was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed. Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating 'flip-flop' kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h). Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.