A Semi-Mechanistic Modeling approach to support Phase III dose selection for TAK-875 Integrating Glucose and HbA1c Data in Japanese Type 2 Diabetes Patients
Fran Stringer (1), Kumi Matsuno (1), Nelleke Snelder (2) and Masashi Hirayama (1)
(1) Clinical Pharmacology Dept, Takeda Pharmaceutical Company, Osaka, Japan; (2) LAP&P Consultants BV, Leiden, The Netherlands;
Objective: TAK-875 is a selective agonist of G protein-coupled receptor 40, and has a different mechanism of action for type 2 diabetes (T2DM) by improving glucose-dependent insulin secretion. This analysis integrated fasting plasma glucose (FPG) and HbA1c to evaluate the drug action of TAK-875 in Japanese T2DM patients. The comprehensive model incorporated placebo effects and was developed to be utilised in the design of the subsequent Phase III clinical trials.
Methods: The efficacy and safety of TAK-875 in T2DM patients were assessed in a Phase II randomized, double-blind study at doses of 6.25, 12.5, 25, 50, 100, and 200mg1. PK and PD data for FPG and HbA1c were collected throughout the trial. The individual PK parameters were estimated in addition to a covariate analysis to explore the influence of different patient characteristics on the exposure of the drug. The relationship between exposure, time, FPG and HbA1c was explored using a simultaneous cascading indirect response model with the measures for individual PK exposure utilised. A number of models were explored to describe the placebo effect.
Results: The observed TAK-875 plasma concentrations were adequately described by a one-compartment model with first order absorption and elimination. Body weight was identified as a covariate on volume. An Emax type exposure-response relationship could be identified for the TAK-875 reductive effect on FPG, with an Emax of 24% and an EC50 of 0.61mg/L, the FPG baseline was estimated as 167mg/dL. The placebo effect was described using a separate Tmax model on the production rate of FPG, capturing both the intervention due to diet and lifestyle in addition to the loss of function due to the washout of previous treatment. Integrating FPG with HbA1c was found to result a lower residual error for HbA1c compared to a model using HbA1c alone, 2.3% vs. 2.49% respectively.
Conclusion: Phase III doses of 25mg and 50mg were selected with the aid of this approach. Combining the description of FPG and HbA1c improved the understanding of the drug effect of TAK-875. Congruent with glucose homeostasis, the drug effect is not on HbA1c, but on glucose regulation mechanisms. However the incorporation of the drug effect on FPG does not fully explain the HbA1c level during treatment with TAK-875. A combined model with FPG and postprandial glucose could further increase the understanding of the novel mechanism of action of TAK-875.
References:
[1] Kaku K, Araki T, Toshinaka R. Randomized, Double-Blind, Dose-Ranging Study of TAK-875, a Novel GPR40 Agonist, in Japanese Patients With Inadequately Controlled Type 2 Diabetes. Diabetes Care. 2013 Feb;36(2):245-50.