BMS-823778 / BMS - LARVOL DELTA

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

Physiologically Based Pharmacokinetic Modeling of a CYP2C19 Substrate, BMS-823778, Utilizing Pharmacogenetic Data. (PubMed, Br J Clin Pharmacol) - "A PBPK model was developed utilizing clinical data that well predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was likely an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely dependent on the genotypes of CYP2C19 and UGT1A4."

Biomarker • Journal • PK/PD data

Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1). (PubMed, ACS Med Chem Lett) - "Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials."

Clinical • Journal