Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood

Abstract

Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which received 1 subcutaneous and 2 intradermal insulin injections on 3 different occasions. The optimal model, selected based on information and posterior identifiability criteria, assumes that insulin is delivered at the administrative site and is then transported to the bloodstream via 2 independent routes (1) diffusion-like process to the blood and (2) combination of diffusion-like processes followed by an additional compartment before entering the blood. This optimal model accounts for biphasic appearance and delayed clearance of exogenous insulin. It agrees better with the clinical data as compared to commonly used models and is expected to improve the in silico development and testing of insulin treatment strategies, including artificial pancreas systems.

The UVA/Padova Type 1 Diabetes Simulator Goes From Single Meal to Single Day

“…Intradermal Insulin. The model of intradermal insulin route is based on Lv et al 33 This model (equations A18, A19) has been identified on 10 healthy subjects, and assumes that insulin delivered at the intradermal site is then transported to the bloodstream via two independent routes, that is, a diffusion-like process and a combination of a diffusion-like processes followed by an additional compartment before entering the blood. Inhaled Insulin.…”

Modeling of Diabetes and Its Clinical Impact

“…It is expected to improve the in silico development and testing of insulin treatment strategies, including AP systems. 25 Diabetes Management With BGM Systems. As it is important to ensure reliability of glucose measurements, there are a number of models that investigate the accuracy of BGM systems and relations to diabetic management.…”

“…It is expected to improve the in silico development and testing of insulin treatment strategies, including AP systems. 25…”

Subcutaneous Insulin Administration: Sufficient Progress or Ongoing Need?

“…Additionally, multicompartment input models have been shown to have better fit to actual clinical PK data, implying parallel uptake pathways. 38,39 This implies that insulin absorption via the lymph may be an underappreciated aspect of insulin uptake. In addition, vascular and lymphatic capillary densities within the tissue, molecular diffusion rates through the extracellular matrix, dissociation rates of various insulins and their specific formulation dependence, and local cellular utilization or degradation may also all contribute to the total uptake during SIA.…”