title: Pharmacometric Approaches to Guide Dose Selection of the Novel GPR40 Agonist TAK-875 in Subjects With Type 2 Diabetes Mellitus.
abstract: 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.
authors.affiliation: Takeda Global Research & Development Center, Inc., Chicago, Illinois, USA.
authors.forename: H
authors.initials: H
authors.lastname: Naik
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: C
authors.initials: C
authors.lastname: Cao
authors.forename: M
authors.initials: M
authors.lastname: Pfister
authors.forename: M
authors.initials: M
authors.lastname: Vakilynejad
authors.forename: E
authors.initials: E
authors.lastname: Leifke