Pharmacometric Approaches to Guide Dose Selection of the Novel GPR40 Agonist TAK‐875 in Subjects With Type 2 Diabetes Mellitus

The G‐protein‐coupled receptor 40 agonist (GPR40) TAK‐875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model‐based exposure‐response and meta‐analyses were applied to (i) characterize exposure/dose–efficacy responses of TAK‐875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) response with TAK‐875 6.25 to 200 mg q.d. doses for 12 weeks, (iii) project and compare HbA1c response with dipeptidyl peptidase 4 (DPP‐4) inhibitors and TAK‐875 up to 24 weeks, and (iv) provide a quantitative rationale for dose selection in phase 3. On the basis of phase 2 data, relationships between TAK‐875 concentrations and HbA1c were well characterized by exposure–response models. EC50 and Emax of TAK‐875 were estimated to be 3.16 µg/ml and 0.366, respectively. Model‐based simulations over 24 weeks indicated that the 25‐ and 50‐mg q.d. doses of TAK‐875 achieve efficacy as comparable with or better than that of commonly used antidiabetic agents. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e22; doi:10.1038/psp.2012.23; advance online publication 9 January 2013