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  • Title: Mechanism-based population modelling of the effects of vildagliptin on GLP-1, glucose and insulin in patients with type 2 diabetes.
    Author: Landersdorfer CB, He YL, Jusko WJ.
    Journal: Br J Clin Pharmacol; 2012 Mar; 73(3):373-90. PubMed ID: 22442825.
    Abstract:
    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.
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