Insulin depot absorption modeling and pharmacokinetic simulation with insulin glargine 300 U/mL

Objective: Mathematical models of insulin absorption have been used to predict plasma insulin concentrations after administration, but few are specifically applicable to insulin glargine, which precipitates subcutaneously after injection. Materials and methods: The formation and redissolution of subcutaneous depots of insulin glargine 100 U/mL (Gla-100) and insulin glargine 300 U/mL (Gla-300) are modeled. Surface-area-dependent redissolution is introduced to established diffusion and absorption pathways, and pharmacokinetic (PK) profiles are simulated and subsequently validated using experimental data from euglycemic glucose clamp studies. Simulations are used to predict the PK effect of adapting the timing of once-daily insulin injections and of switching from one insulin product to the other. Results: Simulated PK profiles resemble those previously observed in clinical trials, with Gla-300 providing more gradual and prolonged release of Gla-300 vs. Gla-100, owing to a more compact depot. The predicted PK profile of Gla-300 shows less fluctuation in plasma insulin concentrations than that of Gla-100, and may be better suited to adapting the timing of daily injections to account for variation in daily activities. Simulating a switch from one insulin glargine product to the other results in temporary alteration of previous steady state, but this is regained within ~ 3 days. Conclusion: This study suggests that PK differences between Gla-300 and Gla-100 are a product of the more compact Gla-300 depot and its smaller surface area. The model employed also allowed estimation of insulin glargine concentrations when varying the time interval between injections as well as when switching from one insulin glargine product to the other.