PI-119 - EUGLYCEMIC CLAMP STUDY DESIGNS FOR NOVEL INSULINS AND INSULIN BIOSIMILARS.

R. Elzein¹, H. Thanukrishnan², M. Nounou³, E. Chow⁴, J. Vaidyanathan³, S. Seo⁴, M. Kronfol³; ¹School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA, Richmond, VA, USA, ²U.S. Food and Drug Administration, Silver Spring MD, USA, ³U.S. Food and Drug Administration, Silver Spring, MD, USA, ⁴U.S. Food and Drug Administration, Silver Spring, USA.

Background: Euglycemic clamp studies are frequently conducted for novel insulin analogs and insulin biosimilars during drug development that provides key pharmacokinetic (PK) and pharmacodynamic (PD) information. Our aim for this study is to scrutinize euglycemic clamp studies published in the literature to gain a better understanding on the most common study design elements that aids in adequate characterization of the PK and PD of insulin.

Methods: Published literature of euglycemic clamp studies from 1993 until 2024 were collected. Study design elements including dosing regimen, insulin type (bolus, basal, or mixture), objectives, demographics, population, and PK and PD sampling schedules and PK/PD endpoints were extracted from the studies. Meta-analysis studies, literature reviews as well as publications for insulins delivered by routes of administration other than parenteral routes were excluded.

Results: A total of 71 studies published in the literature were reviewed. Of the 71 studies, 31 were conducted with bolus, 9 with mixture, and 31 with basal insulin. Most studies utilized single doses in the range of 0.075–1.6 U/kg, 0.18 - 0.8 U/kg, and 0.01-2.22 U/kg for bolus, mixture, and basal insulins. Assessment of relative bioavailability was the most common objective. The mean (range) age, weight, and BMI was 39 years (24-70 years), 75.2 kg (58.3-121.6 kg), and 25.4 kg/m2 (21.5-32.2 kg/m2), with 0-55.2% female participation. Thirty four out of the 71 studies were in healthy volunteers while the remainder were in patients with Type 1 or Type 2 Diabetes. PK sampling for bolus insulin studies was up to 24 hours postdose while up to 30 and 42 hours for mixture and basal insulins. The PK endpoints were similar and included insulin Cmax, Tmax, and AUC. There were 2 primary PD endpoints (maximal Glucose Infusion Rate (GIRmax) and AUCGIR) with the most common duration for PD assessment being every minute.

Conclusion: Euglycemic clamp studies guide novel insulin analogs and insulin biosimilar drug development. In general, most euglycemic clamp studies characterized the time-action profile of these insulin products. Dosing may differ depending on the type of insulin used, while PK/PD endpoints and sampling schedule are very similar within each type of insulin. This can help inform development of future novel insulin analogs and insulin biosimilars.