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A Comprehensive Review of Novel Drug–Disease Models in Diabetes Drug Development

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Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which affects millions of people worldwide. The disease is characterized by chronically elevated blood glucose concentrations (hyperglycaemia), which result in comorbidities and multi-organ dysfunction. This is due to a gradual loss of glycaemic control as a result of increasing insulin resistance, as well as decreasing β-cell function. The objective of T2DM drug interventions is, therefore, to reduce fasting and postprandial blood glucose concentrations to normal, healthy levels without hypoglycaemia. Several classes of novel antihyperglycaemic drugs with various mechanisms of action have been developed over the past decades or are currently under clinical development. The development of these drugs is routinely supported by the application of pharmacokinetic/pharmacodynamic modelling and simulation approaches. They integrate information on the drug’s pharmacokinetics, clinically relevant biomarker information and disease progression into a single, unifying approach, which can be used to inform clinical study design, dose selection and drug labelling. The objective of this review is to provide a comprehensive overview of the quantitative approaches that have been reported since the 2008 review by Landersdorfer and Jusko in an increasing order of complexity, starting with glucose homeostasis models. Each of the presented approaches is discussed with respect to its strengths and limitations, and respective knowledge gaps are highlighted as potential opportunities for future drug–disease model development in the area of T2DM.

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Acknowledgments

The authors would like to thank Roman Götz for his critical input into the manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida at Lake Nona (Orlando), 6550 Sanger Road, Room 467, Orlando, FL, 32827, USA

    Puneet Gaitonde, Catharina Link, Mirjam N. Trame & Stephan Schmidt

  2. Clinical Pharmacology, Global Innovative Pharma, Pfizer Inc., Groton, CT, 06340, USA

    Puneet Gaitonde

  3. Global PK/PD and Pharmacometrics, Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Parag Garhyan & Jenny Y. Chien

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  1. Puneet Gaitonde
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Correspondence to Stephan Schmidt.

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Puneet Gaitonde was supported by a postdoctoral Grant by Eli Lilly and Company, and is currently an employee of Pfizer Inc. Parag Garhyan and Jenny Chien are employees of Eli Lilly and Company, and own stock in Eli Lilly and Company. Catharina Link, Mirjam N. Trame and Stephan Schmidt have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Gaitonde, P., Garhyan, P., Link, C. et al. A Comprehensive Review of Novel Drug–Disease Models in Diabetes Drug Development. Clin Pharmacokinet 55, 769–788 (2016). https://doi.org/10.1007/s40262-015-0359-y

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