TY - JOUR
T1 - Mechanism-based population modelling of the effects of vildagliptin on GLP-1, glucose and insulin in patients with type 2 diabetes
AU - Landersdorfer, Cornelia Barbara
AU - He, Yan-Ling
AU - Jusko, William J
PY - 2012
Y1 - 2012
N2 - Vildagliptin is a potent and selective inhibitor of dipeptidyl
peptidase IV (DPP-4), leading to increased concentrations
of active glucagon-like peptide 1 (GLP-1) and thereby
decreased plasma glucose concentrations. Vildagliptin is
approved for treatment of type 2 diabetes mellitus in more
than 76 countries including the European Union and Japan
where 85 to 95 of all diabetes cases are type 2 [1].
Such patients exhibit insufficient insulin activity due
to decreased insulin action in glucose-utilizing tissues
(peripheral insulin resistance) and impaired insulin secretion
from the b-cells in the pancreas (beta-cell failure).
After ingestion of a meal, GLP-1, an incretin hormone,
is released from the L-cells in the gut wall. Its secretion
is stimulated both by endocrine and neural signals and
by direct stimulation of the intestinal cells by digested
nutrients in the gut. Active GLP-1 stimulates glucosedependent
insulin secretion from b-cells, enhances b-cell
proliferation and increases b-cell resistance to apoptosis
[2]. GLP-1 has also been demonstrated to suppress hepatic
glucose production and delay gastric emptying [3],
thereby decreasing high blood glucose concentrations
after food intake. GLP-1 is rapidly inactivated by the ubiquitous
enzyme DPP-4 with a half-life of approximately
2 min in humans. Reduced secretion of GLP-1 in type 2
diabetic patients compared with healthy subjects has
been reported [4, 5]. Vildagliptin, a DPP-4 inhibitor, prolongs
the action of active GLP-1 by inhibiting its inactivation
by the DPP-4 enzyme.
While the effects of vildagliptin from this study in type
2 diabetic patients were previously described by noncompartmental
analysis (NCA) [6], a mechanism-based
compartmental modelling approach has not been applied.
Simultaneous modelling of PD endpoints such as DPP-4,
GLP-1, insulin and glucose by taking the pathophysiology
into account allows the exploration of the dynamic aspects
of mechanisms of action
AB - Vildagliptin is a potent and selective inhibitor of dipeptidyl
peptidase IV (DPP-4), leading to increased concentrations
of active glucagon-like peptide 1 (GLP-1) and thereby
decreased plasma glucose concentrations. Vildagliptin is
approved for treatment of type 2 diabetes mellitus in more
than 76 countries including the European Union and Japan
where 85 to 95 of all diabetes cases are type 2 [1].
Such patients exhibit insufficient insulin activity due
to decreased insulin action in glucose-utilizing tissues
(peripheral insulin resistance) and impaired insulin secretion
from the b-cells in the pancreas (beta-cell failure).
After ingestion of a meal, GLP-1, an incretin hormone,
is released from the L-cells in the gut wall. Its secretion
is stimulated both by endocrine and neural signals and
by direct stimulation of the intestinal cells by digested
nutrients in the gut. Active GLP-1 stimulates glucosedependent
insulin secretion from b-cells, enhances b-cell
proliferation and increases b-cell resistance to apoptosis
[2]. GLP-1 has also been demonstrated to suppress hepatic
glucose production and delay gastric emptying [3],
thereby decreasing high blood glucose concentrations
after food intake. GLP-1 is rapidly inactivated by the ubiquitous
enzyme DPP-4 with a half-life of approximately
2 min in humans. Reduced secretion of GLP-1 in type 2
diabetic patients compared with healthy subjects has
been reported [4, 5]. Vildagliptin, a DPP-4 inhibitor, prolongs
the action of active GLP-1 by inhibiting its inactivation
by the DPP-4 enzyme.
While the effects of vildagliptin from this study in type
2 diabetic patients were previously described by noncompartmental
analysis (NCA) [6], a mechanism-based
compartmental modelling approach has not been applied.
Simultaneous modelling of PD endpoints such as DPP-4,
GLP-1, insulin and glucose by taking the pathophysiology
into account allows the exploration of the dynamic aspects
of mechanisms of action
UR - http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2011.04109.x/pdf
U2 - 10.1111/j.1365-2125.2011.04109.x
DO - 10.1111/j.1365-2125.2011.04109.x
M3 - Article
SN - 0306-5251
VL - 73
SP - 373
EP - 390
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 3
ER -