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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
Author(s) -
Naik Himanshu,
Vakilynejad Majid,
Wu Jingtao,
Viswanathan Prabhakar,
Dote Nobuhito,
Higuchi Tomoaki,
Leifke Eckhard
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011409230
Subject(s) - tolerability , pharmacokinetics , pharmacodynamics , medicine , placebo , pharmacology , agonist , adverse effect , oral administration , hypoglycemia , crossover study , insulin , receptor , alternative medicine , pathology
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.