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.

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 ß-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.

Stereoselective dissolution of propranolol hydrochloride from hydroxypropyl methylcellulose matrices.

Since many chiral pharmaceutical excipients, such as cellulose polymers and cyclodextrins, are used as stationary phases for the separation of enantiomers by high performance liquid chromatography (HPLC), it is hypothesized that one enantiomer of a chiral drug will be released faster than the other from a pharmaceutical formulation containing a racemic drug and a chiral excipient. The mechanism of such an event may arise from preferential intermolecular interaction between the chiral excipient and one of the enantiomers. To test this hypothesis, the release of the enantiomers of propranolol hydrochloride into water from formulations containing the chiral excipients, hydroxypropyl methylcellulose (HPMC) or beta-cyclodextrin, was investigated by stereospecific HPLC analysis of the dissolved concentrations of each of the enantiomers from the formulations. The release of the enantiomers of propranolol hydrochloride from the formulations containing HPMC, although variable, was found to be stereoselective. However, the release of propranolol hydrochloride enantiomers from the beta-cyclodextrin complex was found to be non-stereoselective.