Christian Hove Rasmussen1, Rikke Meldgaard Røge2, Zhulin Ma3, Maria Thomsen4, Rannveig Linda Thorisdottir5, Jian-Wen Chen6, Erik Mosekilde7, Morten Colding-Jørgensen8. 1. Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark; Department of Physics, Technical University of Denmark, Fysikvej 309, DK-2800 Kgs. Lyngby, Denmark. Electronic address: chvr@novonordisk.com. 2. Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark; Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591, SE-75124 Uppsala, Sweden. 3. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark. 4. Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark; Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark. 5. Ögonkliniken, Skåne University Hospital, Inga-Marie Nilssons gata 38, SE-21428 Malmö, Sweden. 6. Novo Nordisk International Operations A/S, Thurgauerstrasse 36/38, CH-8050 Zürich, Switzerland. 7. Department of Physics, Technical University of Denmark, Fysikvej 309, DK-2800 Kgs. Lyngby, Denmark. 8. Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark.
Abstract
BACKGROUND: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control post-prandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between and within individuals. The present article identifies the main physiological mechanisms that govern the PK of IAsp following subcutaneous administration and quantifies them in terms of their contribution to the overall variability. MATERIAL AND METHODS: CT scanning data from Thomsen et al. (2012) are used to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic distribution and elimination (Pørksen et al., 1997; Sjöstrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b) are analyzed in the nonlinear mixed effects software Monolix® to determine the presence and effects of the mechanisms described in this article. RESULTS: The distribution of IAsp in the subcutaneous depot show an initial dilution of approximately a factor of two in a single experiment. Injected insulin hexamers exist in a chemical equilibrium with monomers and dimers, which depends strongly on the degree of dilution in subcutis, the presence of auxiliary substances, and a variety of other factors. Sensitivity to the initial dilution in subcutis can thus be a cause of some of the variability. Temporal variations in the PK are explained by variations in the subcutaneous blood flow. IAsp antibodies are found to be a large contributor to the variability of total insulin PK in a study by Chen et al. (2005), since only the free fraction is eliminated via the receptors. The contribution of these and other sources of variability to the total variability is quantified via a population PK analysis and two recent clinical studies (Thorisdottir et al., 2009; Ma et al., 2012b), which support the presence and significance of the identified mechanisms. CONCLUSIONS: IAsp antibody binding, oligomeric transitions in subcutis, and blood flow dependent variations in absorption rate seem to dominate the PK variability of IAsp. It may be possible via e.g. formulation design to reduce some of these variability factors.
BACKGROUND:Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control post-prandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between and within individuals. The present article identifies the main physiological mechanisms that govern the PK of IAsp following subcutaneous administration and quantifies them in terms of their contribution to the overall variability. MATERIAL AND METHODS: CT scanning data from Thomsen et al. (2012) are used to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for humaninsulin are used to understand and quantify the systemic distribution and elimination (Pørksen et al., 1997; Sjöstrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b) are analyzed in the nonlinear mixed effects software Monolix® to determine the presence and effects of the mechanisms described in this article. RESULTS: The distribution of IAsp in the subcutaneous depot show an initial dilution of approximately a factor of two in a single experiment. Injected insulin hexamers exist in a chemical equilibrium with monomers and dimers, which depends strongly on the degree of dilution in subcutis, the presence of auxiliary substances, and a variety of other factors. Sensitivity to the initial dilution in subcutis can thus be a cause of some of the variability. Temporal variations in the PK are explained by variations in the subcutaneous blood flow. IAsp antibodies are found to be a large contributor to the variability of total insulin PK in a study by Chen et al. (2005), since only the free fraction is eliminated via the receptors. The contribution of these and other sources of variability to the total variability is quantified via a population PK analysis and two recent clinical studies (Thorisdottir et al., 2009; Ma et al., 2012b), which support the presence and significance of the identified mechanisms. CONCLUSIONS: IAsp antibody binding, oligomeric transitions in subcutis, and blood flow dependent variations in absorption rate seem to dominate the PK variability of IAsp. It may be possible via e.g. formulation design to reduce some of these variability factors.
Authors: Erin J Mansell; Signe Schmidt; Paul D Docherty; Kirsten Nørgaard; John B Jørgensen; Henrik Madsen Journal: J Pharmacokinet Pharmacodyn Date: 2017-08-22 Impact factor: 2.745
Authors: A K J Gradel; T Porsgaard; J Lykkesfeldt; T Seested; S Gram-Nielsen; N R Kristensen; H H F Refsgaard Journal: J Diabetes Res Date: 2018-07-04 Impact factor: 4.011