Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

TAK‐648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA(1c) results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK‐648 to required exposure in humans. A first‐in‐human study with single TAK‐648 doses of 0.05–0.85 mg in healthy volunteers yielded mean maximum TAK‐648 concentrations (Cmax) and area under the curve (AUC) values from 0.62–11.9 μg/L and 4.58–93.8 μg*h/L, respectively. Based on the performed pharmacokinetic/pharmacodynamic analysis and clinical PK results, clinical efficacy would be expected at a daily dose of 0.1 mg, which is well within the investigated clinical dose range. This result significantly enhanced the confidence in TAK‐648 for type 2 diabetes treatment and underlines the necessity of translational approaches in early preclinical phases.