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- Title
Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV.
- Authors
Landersdorfer, Cornelia B.; He, Yan-Ling; Jusko, William J.
- Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is a novel antidiabetic agent that acts by inhibiting dipeptidyl peptidase IV (DPP-4). • DPP-4 inhibition results in higher active concentrations of incretin hormone, glucagon-like peptide 1 (GLP-1), leading to reduced glucose concentrations. • Mechanism-based modelling of the pharmacokinetics (PK) of vildagliptin and its DPP-4 inhibition effects in type 2 diabetic patients has not been performed. WHAT THIS STUDY ADDS • Population pharmacokinetic modelling of the vildagliptin concentrations from three different doses indicated the presence of a small saturable elimination pathway for vildagliptin. • Simultaneous population modelling of the pharmacokinetics and DPP-4 activity in patients with type 2 diabetes after treatment with vildagliptin revealed: 1) Saturable binding of vildagliptin to DPP-4 in plasma and tissues and partial hydrolysis of vildagliptin by DPP-4. 2) Vildagliptin is both an inhibitor and a substrate for DPP-4. 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.
- Subjects
HYPOGLYCEMIC agents; PHARMACOKINETICS; ENZYME inhibitors; PEPTIDASE; BIOLOGICAL models
- Publication
British Journal of Clinical Pharmacology, 2012, Vol 73, Issue 3, p391
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2011.04108.x