The Effect of Multiple Doses of BI 187004 on the Single-dose Pharmacokinetics of Repaglinide and Bupropion Following Oral Administration in Healthy Male Subjects (an Open-label, One-sequence Trial)

To assess the influence of BI 187004 on pharmacokinetics of CYP2C8 and CYP2B6 probe drugs repaglinide and bupropion as a means of predicting drug-drug interactions.

开始日期2014-12-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT02254148 / Completed临床1期

The Effect of Multiple Doses of BI 187004 on the Single Dose Pharmacokinetics of Cytochrome P450 Substrates (Caffeine, Warfarin, Omeprazole, Metoprolol and Midazolam) and a P-glycoprotein Substrate (Digoxin) Administered Orally in an Open-label, One-sequence Trial in Healthy Subjects

To assess the influence of BI 187004 on kinetics of cytochrome P450 (CYP) and P glycoprotein (P-gp) probe drugs as a means of predicting drug-drug interactions.

开始日期2014-10-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT02150824 / Completed临床2期

A Randomized, Double-blind, Placebo-controlled, Parallel Groups Study to Investigate the Safety and Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of Three BI 187004 Doses Given Once Daily as Mono-therapy and of the Highest BI 187004 Dose Given Once Daily as Add on Treatment to Metformin Over 28 Days in Patients With Type 2 Diabetes Mellitus

Assess the safety and tolerability of once daily oral doses of BI 187004 in patients with type 2 diabetes mellitus without oral antidiabetic treatment and in patients on a stable metformin background treatment over 28 days. Assess the effect on fasting plasma glucose after 28 days of treatment and to investigate the pharmacokinetics and pharmacodynamics of BI 187004.

开始日期2014-07-01

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 BI-187004-CL 相关的临床结果

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100 项与 BI-187004-CL 相关的转化医学

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100 项与 BI-187004-CL 相关的专利（医药）

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2023-05-01·The Journal of Clinical Pharmacology

Importance of Target‐Mediated Drug Disposition (TMDD) of Small‐Molecule Compounds and Its Impact on Drug Development—Example of the Class Effect of HSD‐1 Inhibitors

Review

作者: An, Guohua ; Katz, David A.

AbstractWith more potent drug candidates being developed, the incidence of target‐mediated drug disposition (TMDD) in small‐molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small‐molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small‐molecule inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1) using ABT‐384, SPI‐62, MK‐0916, BMS‐823778, and BI‐187004 as case examples. Although developed independently by different pharmaceutical companies, these HSD‐1 inhibitors demonstrated strikingly similar nonlinear pharmacokinetic behaviors when wide dose ranges were evaluated in first‐in‐human (FIH) single ascending dose (SAD) and multiple ascending dose (MAD) studies. Recognizing TMDD in small‐molecule compounds is important, as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. In this review, we summarize the general pharmacokinetic features that facilitate the recognition of small‐molecule TMDD, provide case examples of specific HSD‐1 inhibitors, highlight the importance of recognizing TMDD of small‐molecule compounds during clinical development, and comment on the importance of utilizing pharmacometric modeling to facilitate the quantitative understanding of small‐molecule compounds exhibiting TMDD.

2023-03-01·Diabetes, Obesity and Metabolism

Safety, tolerability, pharmacodynamics and pharmacokinetics following once‐daily doses of BI 187004, an inhibitor of 11 beta‐hydroxysteroid dehydrogenase‐1, over 28 days in patients with type 2 diabetes mellitus and overweight or obesity

Article

作者: Plum‐Mörschel, Leona ; Peil, Barbara ; Bianzano, Susanna ; Heise, Tim ; Nordaby, Matias

AbstractAimsTo study the oral 11 beta‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity.Materials and MethodsThis Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28–40 kg/m2.ResultsIn total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose‐dependently. Target engagement of 11β‐HSD1 was observed with near‐full inhibition of 11β‐HSD1 in the liver [decreased (5α‐tetrahydrocortisol + 5β‐tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic–pituitary–adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p < .05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug‐related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose‐dependent increase in heart rate was seen with BI 187004 treatment.ConclusionsBI 187004 was generally well tolerated in patients with T2DM. Despite complete 11β‐HSD1 inhibition, no clinically relevant effects were observed with BI 187004.

2022-12-01·Experimental and Clinical Endocrinology & Diabetes

Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days

Article

作者: Schepers, Cornelia ; Wolff, Michael ; Plum-Moerschel, Leona ; Bianzano, Susanna ; Heise, Tim

Abstract Objective To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. Methods Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10–360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia.BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106–124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9–99.4% immediately after the second dose and 73.8–97.5% 24 h after the last dose of BI 187004. Conclusions BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity.

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床2期	-	Vitae Pharmaceuticals LLC	-
2型糖尿病	临床2期	-	Vitae Pharmaceuticals LLC	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01587417 (Pubmed)	临床1期	-	72	BI 187004	網觸鑰鑰壓壓鹹觸窪積(積蓋鹹鏇餘窪積簾構繭) = 窪簾網願膚簾襯顧獵鹽鬱觸繭觸網壓糧構艱鑰 (鑰醖醖簾衊廠鹽願醖醖 )	-	2021-08-15