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 mu g 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 mu g/L and 4.58-93.8 mu g*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.