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Mechanism‐based population modelling of the effects of vildagliptin on GLP‐1, glucose and insulin in patients with type 2 diabetes
Author(s) -
Landersdorfer Cornelia B.,
He YanLing,
Jusko William J.
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.04109.x
Subject(s) - vildagliptin , medicine , endocrinology , insulin , type 2 diabetes , population , diabetes mellitus , pharmacology , environmental health
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.