Article date: March 2012
By: Cornelia B. Landersdorfer, Yan‐Ling He, William J. Jusko, in Volume 73, Issue 3, pages 391-401
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.
DOI: 10.1111/j.1365-2125.2011.04108.x
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