Graduate Student University at Buffalo Buffalo, New York, United States
Objectives: To compare the efficacy of different types of subcutaneous insulin, including rapid-acting, intermediate-acting, long-acting, and human regular insulin, using a mechanistic-based pharmacokinetic (PK) and pharmacodynamic (PD) model.
Methods: An established [1] biophase/indirect response model was used to evaluate the effect of insulin on glucose utilization during euglycemic clamp studies and compare the PK and PD parameters between various types of insulin in healthy volunteers. The data were digitized from all published studies that could be found. Healthy subjects received two or three doses of insulin subcutaneously during the glucose clamp and their glucose infusion rates monitored using the Biostator. All data were modeled simultaneously using MONOLIX (Version 2024).
Results: The subcutaneous insulin pharmacokinetics was described by two first-order absorption processes and first-order elimination. Insulin's effect on glucose was described by a combination of a biophase model and an indirect model reflecting insulin stimulation of tissue glucose uptake [1]. The different characteristics of each type of insulin necessitated independent PK parameters estimated. Pharmacodynamic parameters were estimated for all insulin jointly. The Smax depicted the maximum stimulation of glucose utilization, reflecting the efficacy of insulin, and SC50 represented the insulin concentration producing half-maximal stimulation of glucose utilization, indicating the potency of insulin. Pharmacodynamic parameter estimates were 133 for Smax and 873 (pmol/L) for SC50 for insulin aspart, lispro, regular human insulin, neutral protamine hagedorn (NPH) insulin, and insulin glargine, and 3679 for insulin detemir. Notably, insulin detemir showed similar efficacy with lower potency, consistent with the model fitting estimate.
Conclusion: The comprehensive mechanism-based glucose-insulin model showed that most types of insulin demonstrated similar efficacy and potency, except for insulin detemir. The glucose-insulin model with a single set of Smax and SC50 parameters enables clinical optimization of insulin therapy by recognizing that most insulin forms differ markedly in PK but not in their intrinsic effects on glucose utilization.
Citations: [1] Landersdorfer, C. B., & Jusko, W. J. (2010). Pharmacokinetic/pharmacodynamic modeling of glucose clamp effects of inhaled and subcutaneous insulin in healthy volunteers and diabetic patients. Drug Metabolism and Pharmacokinetics, 25(5), 418–429.
