title: 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.
authors.affiliation: Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Dayu
authors.initials: D
authors.lastname: Lv
authors.affiliation: Department of Bioengineering, University of Maryland College Park, College Park, MD, USA.
authors.forename: Sandip D
authors.initials: SD
authors.lastname: Kulkarni
authors.affiliation: Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chan
authors.affiliation: Beckton Dickinson Technologies, Research Triangle Park NC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Keith
authors.affiliation: Beckton Dickinson Technologies, Research Triangle Park NC, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Pettis
authors.affiliation: Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Boris P
authors.initials: BP
authors.lastname: Kovatchev
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
authors.forename: Leon S
authors.initials: LS
authors.lastname: Farhi
authors.affiliation: Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA mb6nt@virginia.edu.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Breton
mesh_terms: D000328:Adult; D000465:Algorithms; D001786:Blood Glucose / Q000032:analysis*; D004058:Diffusion; D005240:Feasibility Studies; D015309:Glucose Clamp Technique; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007267:Injections; D007279:Injections, Subcutaneous; D061268:Insulin Lispro / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008962:Models, Theoretical; D061214:Patient Safety; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D061268:Insulin Lispro
keywords: biphasic kinetics; delayed clearance; fast-acting insulin; pharmacokinetic modeling