Development and Qualification of a Drug-Disease Modeling Platform to Characterize Clinically Relevant Endpoints in Type 2 Diabetes Trials

• Published in: Clinical pharmacology and therapeutics Vol. 104; no. 4; p. 699
• Main Authors: Gaitonde, Puneet, Hurtado, Felipe K, Garhyan, Parag, Chien, Jenny Y, Schmidt, Stephan
• Format: Journal Article
• Language: English
• Published: United States 01.10.2018
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers - blood; Blood Glucose - drug effects; Blood Glucose - metabolism; Clinical Trials as Topic - methods; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - drug therapy; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endpoint Determination; Female; Glycated Hemoglobin A - metabolism; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Insulin - blood; Male; Metformin - therapeutic use; Middle Aged; Models, Biological; Research Design; Sulfonylurea Compounds - therapeutic use; Thiazolidinediones - therapeutic use; Time Factors; Treatment Outcome
• ISSN: 1532-6535
• DOI: 10.1002/cpt.998

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by persistently elevated blood glucose concentration (hyperglycemia). We developed a mechanistic drug-disease modeling platform based on data from more than 4,000 T2DM subjects in seven phase II/III clinical trials. The model integrates longitudinal changes in clinically relevant biomarkers of glycemic control with information on baseline disease state, demographics, disease progression, and different therapeutic interventions, either when given alone or as add-on combination therapy. The model was able to simultaneously characterize changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin A1c following administration of sulfonylurea, metformin, and thiazolidinedione as well as disease progression in clinical trials ranging from 16-104 weeks of treatment. The mechanistic components of this generalized mechanism-based platform, based on knowledge of pharmacology, insulin-glucose homeostatic feedback, and diabetes pathophysiology, allows its application to be further expanded to other antidiabetic drug classes and combination therapies.