title: Preclinical PK/PD modeling and human efficacious dose projection for a glucokinase activator in the treatment of diabetes.
abstract: Human Hexokinase IV, or glucokinase (GK), is a regulator of glucose concentrations in the body. It plays a key role in pancreatic insulin secretion as well as glucose biotransformation in the liver, making it a potentially viable target for treatment of Type 2 diabetes. Allosteric activators of GK have been shown to decrease blood glucose concentrations in both animals and humans. Here, the development of a mathematical model is presented that describes glucose modulation in an ob/ob mouse model via administration of a potent GK activator, with the goal of projecting a human efficacious dose and plasma exposure. The model accounts for the allosteric interaction between GK, the activator, and glucose using a modified Hill function. Based on model simulations using data from the ob/ob mouse and in vitro studies, human projections of glucose response to the GK activator are presented, along with dose and regimen predictions to maintain clinically significant decreases in blood glucose in a Type 2 diabetic patient. This effort serves as a basis to build a detailed mechanistic understanding of GK and its role as a therapeutic target for Type 2 diabetes, and it highlights the benefits of using such an approach in a drug discovery setting.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, 10646 Science Center Drive, San Diego, CA, USA, mgzager@gmail.com.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Zager
authors.forename: Kirk
authors.initials: K
authors.lastname: Kozminski
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pascual
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
mesh_terms: D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D020536:Enzyme Activators / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008954:Models, Biological
chemical_list: D001384:Azetidines; D001572:Benzofurans; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; C000592278:PF-04279405; D005941:Glucokinase