St. John’s University Foster City, California, United States
Background: The objective of this analysis was to develop a translational minimal physiologically based pharmacokinetic/pharmacodynamic (m-PBPK/PD) model by considering both the blood flow (perfusion) and permeability of the cell membrane, to quantify the relationship between insulin disposition, and subsequent glucose reduction. The m-PBPK/PD model was applied to estimate the first-in-human (FIH) therapeutic dose range and regimen selection in pediatric patients with Type 1 diabetes. Methods: The minimal-PBPK/PD model development makes use of published PK data of insulin and glucose reduction. The data comprise of insulin plasma concentration measurements after an intravenous administration of regular human insulin to healthy Yucatan minipigs (n = 12) (after an overnight fasting), at a dose of 0.1 IU kg1. Plasma concentration-time profiles of insulin in minipigs was modelled using m-PBPK model. Insulin responsive blood glucose reductions were fitted as a linear function of plasma insulin levels using transit compartment model for signal transduction processes with associated time delays. The final model (with covariates) was selected for FIH PK/PD prediction. Results: The m-PBPK and m-PBPK/PD model converged successfully with physiologically plausible parameter estimates, estimated with reasonable %RSE ( < 30%). The inter-individual variability of the glucose reduction was 0.62%. The translational m-PBPK/PD model was scaled to human via allomtric scaling of model parameters to predict insulin exposure in pediatrics. Efficacious dose range and regimen were evaluated based on non-inferiority of the predicted glucose reduction. Conclusion: The m-PBPK/PD model adequately described observed responses without any systemic bias.
