title: A Comprehensive Review of Novel Drug-Disease Models in Diabetes Drug Development.
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.
authors.affiliation: 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.|Clinical Pharmacology, Global Innovative Pharma, Pfizer Inc., Groton, CT, 06340, USA.
authors.forename: Puneet
authors.initials: P
authors.lastname: Gaitonde
authors.affiliation: Global PK/PD and Pharmacometrics, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Parag
authors.initials: P
authors.lastname: Garhyan
authors.affiliation: 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.
authors.forename: Catharina
authors.initials: C
authors.lastname: Link
authors.affiliation: Global PK/PD and Pharmacometrics, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Jenny Y
authors.initials: JY
authors.lastname: Chien
authors.affiliation: 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.
authors.forename: Mirjam N
authors.initials: MN
authors.lastname: Trame
authors.affiliation: 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. sschmidt@cop.ufl.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
mesh_terms: D015415:Biomarkers; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D005941:Glucokinase / Q000096:biosynthesis; D006442:Glycated Hemoglobin; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D054795:Incretins / Q000096:biosynthesis; D007328:Insulin / Q000378:metabolism; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D000077203:Sodium-Glucose Transporter 2 Inhibitors