Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK-648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction.
Clin Transl Sci
; 10(3): 185-193, 2017 05.
Article
in En
| MEDLINE
| ID: mdl-28088839
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 HbA1c 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 2
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Translational Research, Biomedical
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Phosphodiesterase 4 Inhibitors
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Models, Biological
Type of study:
Clinical_trials
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Prognostic_studies
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Risk_factors_studies
Limits:
Adult
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Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Clin Transl Sci
Year:
2017
Document type:
Article
Affiliation country:
Switzerland
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA