170: A Target-mediated Drug Disposition Model to Explain the Nonlinear Pharmacokinetics of the 11-Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor BI-187004 in Healthy Subjects

Statement of Purpose: Long-term sustained high cortisol levels can cause central obesity, type 2 diabetes, hypertension and other cardiovascular risk factors. The intracellular enzyme 11beta-hydroxysteroid dehydrogenase-1 (11β-HSD1) provides a mechanism for metabolically important tissues to convert biologically inactive cortisone to active cortisol. Increasing evidence has indicated that reducing cortisol generation through 11β-HSD1 inhibition could be a promising therapeutic strategy for type-2 diabetes and obesity. BI-187004 is a selective and small-molecule 11β-HSD1 inhibitor characterized by complex nonlinear pharmacokinetics (PK) in humans at low single-dose and linear PK at higher doses. A maximum of 70% 11β-HSD1 inhibition was achieved in a relatively high-dose group, remaining on this level in all higher treatment groups. However, substantial 11β-HSD1 inhibition (80% of the maximum inhibition observed in high doses) was detected in a very low-dose group. BI-187004’s unusual pharmacokinetics and pharmacodynamics imply the exhibition of pharmacological targeted-mediated drug disposition (TMDD) caused by the saturable binding of a selective compound to its high-affinity-low-capacity pharmacological target. Due to its unusual nonlinear PK, the relationship among BI-187004 dose, exposure and response is no longer intuitive, and dose selection will be challenging. This study aimed to construct a population PK model to characterize the complex nonlinear PK behavior and perform simulation under different dosing regimens to facilitate the selection of optimal dosing regimens of BI187004.

Description of Methods & Materials: Data used in this study came from a published clinical study investigating BI-187004 in healthy males with overweight or obesity following single ascending doses (2.5, 5, 10, 20, 40, 80, 160, 240 and 360 mg). A total of 918 plasma samples from 71 subjects in nine dose cohorts were analyzed. We used the first-order conditional estimation method with interaction and a user-defined subroutine ADVAN13 in NONMEM 7.4.3 to estimate the population values of PK parameters, interindividual variability and residual variability. We used SAS 9.4 and SigmaPlot 13.0 for data analysis and visualization.

Data & Results: Among various models we tested, the best model to characterize BI-187004 PK behavior was a two-compartment TMDD model with three transit absorption compartments. This TMDD model described BI-187004 adequately at both the individual and population levels. The estimated total amount of the 11β-HSD1 enzyme (Rtotal) was 7950 nmol, which aligned with the estimated Rtotal value from other published studies of 11β-HSD1. The model results indicated that BI-187004 interacted with 11β-HSD1 with an association rate constant of 0.095 nM/hr and a dissociation rate constant of 0.106 1/hr. The final model calculated the target occupancy in each dose: 80% target occupancy in the 2.5 mg group and almost 100% target occupancy in all higher groups. These model-informed results coincided with the clinical outcomes that a very low dose of BI287004 generated 80% of 11β-HSD1 inhibition, related to the peak inhibition activity induced in high-dose groups.

Interpretation, Conclusion or Significance: Our final population PK model successfully captured the complex nonlinear PK of the small-molecule compound BI-187004 and provided valuable insight into the mechanism of 11β-HSD1-mediated drug disposition. Our modeling work may represent a helpful reference in rational dose regimen selection for future BI-187004 clinical trials.

Disclosures: The authors declare no conflicts of interest.