Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11 β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model

This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11 h-1). 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.PMID:38652112 | DOI:10.1002/jcph.2438
Source: The Journal of Clinical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research