BI-187004 / AbbVie - LARVOL DELTA

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model. (PubMed, J Clin Pharmacol) - "Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials."

Journal • PK/PD data

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. (PubMed, Diabetes Obes Metab) - P2 | "BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11β-HSD1 inhibition, no clinically relevant effects were observed with BI 187004."

Journal • PK/PD data • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Pain • Type 2 Diabetes Mellitus

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. (PubMed, J Clin Pharmacol) - "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, MK0916, BMS-823778, and BI-187004 as case examples. 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 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 quantitative understanding of small-molecule compounds exhibiting TMDD."

Journal

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. (PubMed, Exp Clin Endocrinol Diabetes) - P1 | "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."

Clinical • Journal • PK/PD data • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • Ventricular Tachycardia

Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity. (PubMed, Clin Diabetes Endocrinol) - P1 | "BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue."

Clinical • Journal • PK/PD data • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Pharmacological evaluation of adipose dysfunction via 11β-hydroxysteroid dehydrogenase type 1 in the development of diabetes in diet-induced obesity mice with cortisone pellet implantation (J Pharmacol Exp Ther) - "...the adipose mRNA level of 11β-HSD1 was up-regulated in DIO/CP mice compared with sham-operated DIO mice...findings also indicate the possibility of a vicious circle of GC signals via 11β-HSD1 up-regulation in adipose tissues contributing to deterioration of the glucose metabolism to result in diabetes."

Preclinical • Diabetes