A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes.
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.
Takeda Global Research & Development Center, Inc., Deerfield, Illinois, USA. eleifke@tgrd.com
E
E
Leifke
H
H
Naik
J
J
Wu
P
P
Viswanathan
D
D
Demanno
M
M
Kipnes
M
M
Vakilynejad
D000284:Administration, Oral; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism / Q000493:pharmacokinetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome
D001572:Benzofurans; D001786:Blood Glucose; D002096:C-Peptide; C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875