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A Multiple‐Ascending‐Dose Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of a Novel GPR40 Agonist, TAK‐875, in Subjects With Type 2 Diabetes
Author(s) -
Leifke E,
Naik H,
Wu J,
Viswanathan P,
DeManno D,
Kipnes M,
Vakilynejad M
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2012.43
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , medicine , agonist , type 2 diabetes , anesthesia , diabetes mellitus , receptor , endocrinology
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. Clinical Pharmacology & Therapeutics (2012); 92 1, 29–39. doi: 10.1038/clpt.2012.43