Mechanism‐based population modelling of the effects of vildagliptin on GLP‐1, glucose and insulin in patients with type 2 diabetes

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? Vildagliptin is a potent and selective inhibitor of dipeptidylpeptidase-IV (DPP-4).? DPP-4 inhibition leads to increased active glucagon-like peptide 1 (GLP-1) concentrations and decreased plasma glucose in patients with type 2 diabetes.WHAT THIS STUDY ADDS? No mechanism-based population PD modelling has been conducted to understand the effects of vildagliptin on active GLP-1, glucose and insulin.? Active GLP-1 concentrations could be described by secretion of active GLP-1 from the gut in response to a meal and elimination by DPP-4 and an additional non-saturable elimination pathway.? The effects of vildagliptin on glucose and insulin are primarily via enhanced GLP-1 concentrations which could be modelled by its effects on insulin secretion and peripheral insulin sensitivity.? Parallelized S-ADAPT but not NONMEM VI proved to be an excellent choice for estimating a complex population model such as the current PK/PD model.AIM To build a mechanism-based population pharmacodynamic model to describe and predict the time course of active GLP-1, glucose and insulin in type 2 diabetic patients after treatment with various doses of vildagliptin.METHODS Vildagliptin concentrations, DPP-4 activity, active GLP-1, glucose and insulin concentrations from 13 type 2 diabetic patients after oral vildagliptin doses of 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. The population PK/PD model was developed utilizing the MC-PEM algorithm in parallelized S-ADAPT version 1.56.RESULTS In the PD model, active GLP-1 production was stimulated by gastrointestinal intake of nutrients. Active GLP-1 was primarily metabolized by DPP-4 and an additional non-saturable pathway. Increased plasma glucose stimulated secretion of insulin which stimulated utilization of glucose. Active GLP-1 stimulated both glucose-dependent insulin secretion and insulin-dependent glucose utilization. Complete inhibition of DPP-4 resulted in an approximately 2.5-fold increase of active GLP-1 half-life.CONCLUSIONS The effects of vildagliptin in patients with type 2 diabetes on several PD endpoints were successfully described by the proposed model. The mechanisms of vildagliptin on glycaemic control could be evaluated from a variety of aspects such as effects of DPP-4 on GLP-1, effects of GLP-1 on insulin secretion and effects on hepatic and peripheral insulin sensitivity. The present model can be used to predict the effects of other dosage regimens of vildagliptin on DPP-4 inhibition, active GLP-1, glucose and insulin concentrations, or can be modified and applied to other incretin-related anti-diabetes therapies.