title: Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK-648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction.
abstract: 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 HbA1cresults 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.
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Plock
authors.affiliation: Institute for Pharmacology and Preclinical Drug Safety, Nycomed GmbH, Barsbüttel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vollert
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, Illinois, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mayer
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Hanauer
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Lahu
mesh_terms: D000328:Adult; D000631:Aminopyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D003521:Cyclopropanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D057170:Translational Research, Biomedical
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast