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Identification of the primary mechanism of action of an insulin secretagogue from meal test data in healthy volunteers based on an integrated glucose-insulin model

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Abstract

The integrated glucose–insulin (IGI) model is a previously developed semi-mechanistic model that incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. It has been shown to adequately describe insulin and glucose profiles in both type 2 diabetics and healthy volunteers following various glucose tolerance tests. The aim of this study was to investigate the ability of the IGI model to correctly identify the primary mechanism of action of glibenclamide (Gb), based on meal tolerance test (MTT) data in healthy volunteers. IGI models with different mechanism of drug action were applied to data from eight healthy volunteers participating in a randomized crossover study with five single-dose tests (placebo and four drug arms). The study participants were given 3.5 mg of Gb, intravenously or orally, or 3.5 mg of the two main metabolites M1 and M2 intravenously, 0.5 h prior to a standardized breakfast with energy content of 1800 kJ. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed using NONMEM®. Drug effects that increased insulin secretion resulted in the best model fit, thus identifying the primary mechanism of action of Gb and metabolites as insulin secretagogues. The model also quantified the combined effect of Gb, M1 and M2 to have a fourfold maximal increase on endogenous insulin secretion, with an EC50 of 169.1 ng mL−1 for Gb, 151.4 ng mL−1 for M1 and 267.1 ng mL−1 for M2. The semi-mechanistic IGI model was successfully applied to MTT data and identified the primary mechanism of action for Gb, quantifying its effects on glucose and insulin time profiles.

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Acknowledgments

The authors would like to thank Vincent Madelain from the University of Poitiers in France for contributing to the individual PK parameter predictions used in this study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Biosciences, Pharmacometrics Research Group, Uppsala University, Box 591, 751 24, Uppsala, Sweden

    Steve Choy, Emilie Hénin, Jan-Stefan van der Walt, Maria C. Kjellsson & Mats O. Karlsson

  2. Faculté de Médecine, Université Claude Bernard Lyon 1, Lyon, France

    Emilie Hénin

  3. Astellas Pharma Europe Ltd, Leiderdorp, The Netherlands

    Jan-Stefan van der Walt

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  1. Steve Choy
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  2. Emilie Hénin
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  3. Jan-Stefan van der Walt
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  4. Maria C. Kjellsson
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  5. Mats O. Karlsson
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Correspondence to Steve Choy.

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Choy, S., Hénin, E., van der Walt, JS. et al. Identification of the primary mechanism of action of an insulin secretagogue from meal test data in healthy volunteers based on an integrated glucose-insulin model. J Pharmacokinet Pharmacodyn 40, 1–10 (2013). https://doi.org/10.1007/s10928-012-9281-1

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  • DOI: https://doi.org/10.1007/s10928-012-9281-1

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