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.

Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

“…Zero-order production rate constant and firstorder loss rate constant for HbA1c were 0.00151/h and 0.00146/h, respectively. The estimate of koutHb was about 3-fold 0.000502/h reported by Naik et al (25) and was similar to 0.00123/h (0.207/ weeks) reported by Gibbs et al (29). The estimated first-order loss rate constant for HbA1c corresponds to a half-life of 2.8 weeks.…”

“…PD Modeling: Two PD models including effects of exenatide ER on FPG as well as incorporating FPG/ HbA1c inter-regulations (25) are developed as depicted in Fig. 1.…”

Exploratory Literature Meta‐Analysis to Characterize the Relationship Between Early and Longer Term Body Weight Loss for Antiobesity Compounds

“…Meta‐regression analyses and other model‐based meta‐analyses can facilitate integration and utilization of summary‐level efficacy and safety data, providing a quantitative framework for comparative efficacy and safety assessment. Several pharmaceutical companies applied such approaches successfully to support study design and dose selections in several therapeutic areas . The primary objective of this meta‐regression analysis was to leverage publically available clinical outcomes data from antiobesity drugs already approved for marketing or in late‐stage clinical trials to: (i)characterize the relationship between very‐short‐term (4‐week) and longer term (3‐ to 6‐month) efficacy in terms of body weight loss. (ii)investigate if this relationship is consistent across antiobesity compounds. (iii)identify and quantify key covariate effects on this relationship. (iv)understand the potential utility of shorter proof‐of‐mechanism studies in the drug development decision‐making process. …”

Model‐Based Approach to Predict Adherence to Protocol During Antiobesity Trials

“…In a second step, the drug effect (E) was incorporated into the model on BW disease progression (BW prog,1 ) using an additional DTPD function . Several drug effect models were evaluated to describe the exposure‐response relationship of naltrexone and bupropion such as slope and E max drug effect relationships.…”