Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of the GPR40 Agonist TAK‐875: Results From a Double‐Blind, Placebo‐Controlled Single Oral Dose Rising Study in Healthy Volunteers

Abstract

TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK-875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(1/2) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK-875 with a high-fat meal decreased C(max) of TAK-875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose-dependent pattern was observed. In healthy volunteers, no glucose-lowering effect and no increase in insulin or c-peptide secretion were evident following administration of TAK-875; the frequency of plasma glucose concentrations <70 mg/dL was similar in the TAK-875 and pooled placebo groups. TAK-875 was well tolerated in the study and has pharmacokinetic characteristics suitable for a once-daily regimen. The pharmacodynamic data support the notion that TAK-875, if effective in diabetic patients, may bear a low risk of hypoglycemia.

Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas

“…To determine if chronic treatment with fasiglifam results in the similar secondary loss of its glucose-lowering efficacy, an oral glucose tolerance test was performed in N-STZ-1.5 rats after long-term multiple doses of fasiglifam. Based on the pharmacokinetic profiles in rats, 3 to 10 mg/kg of fasiglifam was selected in the following study; this dose is close to the clinical doses of fasiglifam in humans (Negoro et al, 2010;Naik et al, 2012). After 14 weeks of treatment (1 week before an oral glucose tolerance test), no significant effects on changes in body weight were observed between vehicle and fasiglifam groups (changes in body weight from initial values: vehicle, 71.3 6 4.8 g; fasiglifam, 68.4 6 5.7 g).…”

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

“…A number of potent GPR40 synthetic ligands have been reported (Christiansen et al, 2008;Sasaki et al, 2011;Walsh et al, 2011), including two agonists that have entered the clinic, [(3S)-6-({2Ј,6Ј-dimethyl-4Ј-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875) (Araki et al, 2012;Naik et al, 2012) and (S)-3(-4-((4Ј-(trifluoromethyl)-[1,1Ј-biphenyl]-3-yl)methoxy) phenyl) hex-4-ynoic acid (AMG 837) (Lin et al, 2011).…”

TAK-875, an Orally Available G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist, Enhances Glucose-Dependent Insulin Secretion and Improves Both Postprandial and Fasting Hyperglycemia in Type 2 Diabetic Rats

“…TAK-875 was also well tolerated after the administration of a single oral dose in healthy volunteers and has pharmacokinetic characteristics suitable for a once-daily regimen (Naik et al, 2011). The current study was conducted to evaluate the cellular signaling events induced by TAK-875 and the pharmacological effects in various in vitro and in vivo models and to determine whether TAK-875 affects ␤ cell function and survival via the prolonged activation of GPR40/FFA 1 , as has been observed with FFAs.…”