PI-116 - APPRAISAL OF PHARMACODYNAMIC CLAMP STUDY DESIGN FOR GLP-1 RECEPTOR AGONISTS.
Wednesday, May 28, 2025
5:00 PM - 6:30 PM East Coast USA Time
J. Lim1, E. Chow2, M. Nounou3, J. Vaidyanathan3, S. Seo2, M. Kronfol3; 1College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA, New York, New York, USA, 2U.S. Food and Drug Administration, Silver Spring, USA, 3U.S. Food and Drug Administration, Silver Spring, MD, USA.
Clinical Pharmacologist U.S. Food and Drug Administration, Maryland, United States
Background: Incretin-based therapy gained significant interest in the fields of Diabetes and Obesity over the last decade. Clinical pharmacology studies have supported their approval for use in the US. Clamp studies provide clinical pharmacology information during drug development. Our aim is to summarize these clamp studies published in the literature to gain a better understanding on the best design to evaluate pharmacodynamics (PD) incretin-based therapy. Methods: Published literature of (1) hyperinsulinemic euglycemic, (2) hyperglycemic, and (3) hypoglycemic clamp studies from 2002 until 2024 were collected. Study design elements including dosing regimen, route of administration (ROA), objectives, demographics, population, and pharmacokinetic (PK) and PD sampling schedules and PK/PD endpoints were extracted. Meta-analysis studies and literature reviews were excluded. Results: A total of 45 studies published in the literature were reviewed. Most studies utilized multiple dose levels (Table 1). Assessment of insulin sensitivity and secretion was the common objective. Baseline characteristics like age, weight, BMI, and % female participation are reported in Table 1. Twenty eight out of the 45 studies were in type 2 diabetes, 9 studies in type 1 diabetes, 3 studies in obesity, and 6 studies in healthy subjects. The most common route was the subcutaneous (SC) ROA. The PK endpoints assessed were similar between semaglutide and liraglutide and included AUC, Cmax, tmax, and t1/2. The PK of liraglutide was assessed up to 60 hrs and up to 840 hrs for semaglutide. The primary PD endpoints were glucose infusion rate (GIR), insulin secretion rate (ISR), first and second phase C-peptide secretion, and concentrations of glucose, insulin, glucagon, and counter-regulatory hormones, with the most common duration for PD assessment being every 5 or 15 min. Conclusion: Clamp studies are frequently used to guide drug development of incretin-based therapy. Most clamps characterized insulin secretion and sensitivity across the class. Dosing may differ depending on the specific drug within the class while the population is either healthy subjects, type 1 diabetes, type 2 diabetes, or obesity. This may help inform development of future novel incretin-based therapy through (1) hyperinsulinemic euglycemic, (2) hyperglycemic, and (3) hypoglycemic clamp studies.