Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

Br J Clin Pharmacol. 2012 Mar;73(3):391-401. doi: 10.1111/j.1365-2125.2011.04108.x.

Abstract

Aims: To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.

Methods: Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.

Results: A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).

Conclusions: Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacokinetics
  • Adamantane / pharmacology
  • Administration, Oral
  • Adult
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Nitriles / pharmacokinetics*
  • Nitriles / pharmacology
  • Pyrrolidines / pharmacokinetics*
  • Pyrrolidines / pharmacology
  • Vildagliptin

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Nitriles
  • Pyrrolidines
  • Dipeptidyl Peptidase 4
  • Vildagliptin
  • Adamantane