Modeling Between-Subject Variability in Subcutaneous Absorption of a Long-Acting Insulin Glargine 100 U/mL by a Nonlinear Mixed Effects Approach

Subcutaneous insulin absorption is well-known to vary significantly both between and within subjects (BSV and WSV, respectively). This variability considerably obstacles the establishing of a reproducible and effective insulin therapy. Some models exist to describe the subcutaneous kinetics of both fast and long-acting insulin analogues; however, none of them account for the BSV. The aim of this study is to develop a nonlinear mixed effects model able to describe the BSV observed in the subcutaneous absorption of a long-acting insulin glargine 100 U/mL. Four stochastic models of the BSV were added to a previously validated model of subcutaneous absorption of insulin glargine 100 U/mL. These were assessed on a database of 47 subjects with type 1 diabetes. The best model was selected based on residual analysis, precision of the estimates and parsimony criteria. The selected model provided good fit of individual data, precise population parameter estimates and allowed quantifying the BSV of the insulin glargine 100 U/mL pharmacokinetics. Future model development will include the description of the WSV of long- acting insulin absorption.