A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes

• Published in: Clinical pharmacology and therapeutics Vol. 92; no. 1; p. 29
• Main Authors: Leifke, E, Naik, H, Wu, J, Viswanathan, P, Demanno, D, Kipnes, M, Vakilynejad, M
• Format: Journal Article
• Language: English
• Published: United States 01.07.2012
• Subjects: Administration, Oral; Benzofurans - administration & dosage; Benzofurans - pharmacology; Biological Availability; Blood Glucose - metabolism; C-Peptide - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Fatty Acids, Nonesterified - metabolism; Glucose Tolerance Test - adverse effects; Glucose Tolerance Test - methods; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Insulin - metabolism; Insulin - pharmacokinetics; Insulin Secretion; Insulin-Secreting Cells - metabolism; Receptors, G-Protein-Coupled - metabolism; Sulfones - administration & dosage; Sulfones - pharmacology; Treatment Outcome
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2012.43

G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.