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Insulin aspart pharmacokinetics: An assessment of its variability and underlying mechanisms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2014 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 62, 65-75 p.Article, review/survey (Refereed) Published
Abstract [en]

Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial 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 (Porksen et al., 1997; Sjostrand 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 (R) 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. (C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
2014. Vol. 62, 65-75 p.
Keyword [en]
Insulin aspart, Subcutaneous injections, Insulin variability, Insulin antibodies, Insulin pharmacokinetics
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-231475DOI: 10.1016/j.ejps.2014.05.010ISI: 000340301500009OAI: oai:DiVA.org:uu-231475DiVA: diva2:745536
Available from: 2014-09-10 Created: 2014-09-08 Last updated: 2016-04-12Bibliographically approved
In thesis
1. Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
Open this publication in new window or tab >>Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several models have been developed for describing the glucose-insulin system. Silber and Jauslin developed a semi-mechanistic integrated glucose insulin (IGI) model which simultaneously describe glucose and insulin profiles in either healthy subjects or type 2 diabetis mellitus (T2DM) patients. The model was developed for describing the basal system, i.e. when no drugs are present in the body. In this thesis the IGI model was extended to also include the effects of anti-diabetic drugs on glucose homeostasis. The model was extended to describe postprandial glucose and insulin excursions in T2DM patients treated with either biphasic insulin aspart or the GLP-1 receptor agonist liraglutide. These extensions make the model a useful tool in drug development as it can be used for elucidating the effects of new products as well as for clinical trial simulation. In this thesis several modelling tasks were also performed to get a more mechanistic description of the glucose-insulin system. A model was developed which describes the release of the incretin hormones glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 following the ingestion of various glucose doses. The effects of these hormones on the beta cell function were incorporated in a model describing both the C-peptide and insulin concentrations in healthy subjects and T2DM patients during either an oral glucose tolerance test or an isoglycaemic intravenous glucose infusion. By including measurements of both C-peptide and insulin concentrations in the model it could also be used to characterize the hepatic extraction of insulin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 212
Glucose homeostasis, Type 2 diabetes, IGI model, Mechanismbased, NONMEM, pharmacometrics
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-274239 (URN)978-91-554-9499-5 (ISBN)
Public defence
2016-04-25, Room B42 in A4, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2016-04-04 Created: 2016-01-20 Last updated: 2016-04-12

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Meldgaard Roge, Rikke
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