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

Diabetes, Obesity & Metabolism
S FreudeU Graefe-Mody

Abstract

To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, after single- and repeated-dose administration. The single-dose study included open-label administration of 200 mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200 mg BI 135585 or placebo once daily over 14 days in patients with type 2 diabetes (T2DM). Assessments included 11β-HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus-pituitary-adrenal (HPA) axis hormone levels. No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5-200 mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65 h. The urinary THF/THE ratio decreased, indicating liver 11β-HSD1 inhibition. Median 11β-HSD1 enzyme inhibition in the...Continue Reading

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Citations

Sep 16, 2020·Diabetes Therapy : Research, Treatment and Education of Diabetes and Related Disorders·Zhiwei ZengTao Sun
Oct 29, 2017·The American Journal of the Medical Sciences·Xia LiShiying Shao
Jun 19, 2021·The Journal of Clinical Endocrinology and Metabolism·Satoko OdaMasatoshi Nomura
Jul 12, 2019·Journal of Medicinal Chemistry·Taotao LingFatima Rivas

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