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

Xuanzhen Yuan; Guohua An

doi:10.1002/jcph.2438

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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

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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

Xuanzhen Yuan and Guohua An

Journal of clinical pharmacology, Vol.64(8), pp.993-1005

07/28/2024

DOI: 10.1002/jcph.2438

PMID: 38652112

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Abstract

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-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 11β-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 11β-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 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 h), and the first-order dissociation rate constant (estimated to be 0.11 h). 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.

BI 187004

nonlinear pharmacokinetics

11β‐hydroxysteroid dehydrogenase type 1 inhibitor

drug development

small‐molecule target‐mediated drug disposition

population PK modeling

UIOWA OA Agreement

Details

Title: Subtitle: 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
Creators: Xuanzhen Yuan - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
Guohua An - University of Iowa
Resource Type: Journal article
Publication Details: Journal of clinical pharmacology, Vol.64(8), pp.993-1005
DOI: 10.1002/jcph.2438
PMID: 38652112
NLM abbreviation: J Clin Pharmacol
eISSN: 1552-4604
Publisher: Wiley
Language: English
Electronic publication date: 04/23/2024
Date published: 07/28/2024
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984618625802771

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