A drug and disease model for lixisenatide, a GLP-1 receptor agonist in type 2 diabetes

Incretin hormone analogs such as glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising new options for the treatment of type 2 diabetes mellitus (T2DM), targeting several of its pathophysiological traits, including reduced insulin sensitivity, inadequate insulin secretion, and...

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Bibliographic Details
Published inJournal of clinical pharmacology Vol. 54; no. 3; p. 267
Main Authors Wilkins, Justin J, Dubar, Michel, Sébastien, Bernard, Laveille, Christian
Format Journal Article
LanguageEnglish
Published England 01.03.2014
Subjects
Adult
Aged
Biomarkers - blood
Blood Glucose - analysis
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Female
Glucagon-Like Peptide-1 Receptor
Glycated Hemoglobin A - analysis
Humans
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Insulin - blood
Male
Middle Aged
Models, Biological
Peptides - pharmacology
Peptides - therapeutic use
Receptors, Glucagon - agonists
model
GLP-1
FPG
disease progress
lixisenatide
HbA1c
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Summary:Incretin hormone analogs such as glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising new options for the treatment of type 2 diabetes mellitus (T2DM), targeting several of its pathophysiological traits, including reduced insulin sensitivity, inadequate insulin secretion, and loss of β-cell mass (BCM). This article describes the semi-mechanistic modeling of lixisenatide dose-response over time using fasting plasma glucose (FPG), fasting serum insulin (FSI) and glycated hemoglobin (HbA1c) data from two Phase II and four Phase III clinical trials, for a total of 2470 T2DM patients. Previously published models for FPG, FSI, and BCM as well as HbA1c were adapted and expanded to describe the available data. The model incorporated aspects describing disease progression, standard-of-care, FPG-dependent and -independent HbA1c synthesis, and covariate effects of body size, race, and sex. The final model described lixisenatide effects on β-cell responsiveness, insulin sensitivity and FPG-independent HbA1c synthesis, was able to describe the observed FPG, FSI, and HbA1c data accurately, and was successful in predicting data from an unseen Phase III clinical study.
ISSN:1552-4604
DOI:10.1002/jcph.192