Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model.
J Clin Pharmacol
; 64(8): 993-1005, 2024 Aug.
Article
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| MEDLINE
| ID: mdl-38652112
ABSTRACT
BI 187004, a selective small-molecule inhibitor of 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11ß-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11ß-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. 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 11ß-HSD1 binding-related parameters for BI 187004, including the total amount of 11ß-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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1
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Relación Dosis-Respuesta a Droga
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Modelos Biológicos
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos