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 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.