Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (HSD1) inhibitor in humans: liver and adipose tissue 11β‐HSD1 inhibition after acute and multiple administrations over 2 weeks

• DOI: 10.1111/dom.12635
• Publication Date: 2016-01-22T14:02:51Z
• Authors: S. Freude; T. Heise; H.‐J. Woerle; A. Jungnik; T. Rauch; B. Hamilton; C. Schölch; F. Huang; U. Graefe‐Mody
• Keywords: Pharmacodynamics

To assess the safety and pharmacokinetic pharmacodynamic characteristics of BI 135585, a selective 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, after single- repeated-dose administration.The single-dose study included open-label administration 200 mg 135585 in healthy volunteers, while multiple-dose study, we carried out randomized, double-blind 5-200 or placebo once daily over 14 days patients with type 2 diabetes (T2DM). Assessments 11β-HSD1 inhibition liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) subcutaneous adipose tissue (AT) ex vivo determination hypothalamus-pituitary-adrenal (HPA) axis hormone levels.No major issues occurred administration. The HPA was mildly activated slightly increased, but still normal adrenocorticotropic levels, increased total urinary corticoid excretion unchanged plasma cortisol levels. After multiple doses exposure (area under curve) dose-proportionally half-life 55-65 h. THF/THE ratio decreased, indicating inhibition. Median enzyme AT reached 90% single dose low (31% lower) continuous treatment.BI safe well tolerated can be dosed daily. Future studies are required to clarify therapeutic potential view its effects on doses. Enzyme not adequately predicted by ratio.