Population Target-Mediated Pharmacokinetic/Pharmacodynamic Modeling to Evaluate SPI-62 Exposure and Hepatic 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition in Healthy Adults

Abstract

Introduction SPI-62 is a small-molecule 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor exhibiting complicated nonlinear pharmacokinetics (PK) in human. Previously, we developed a target-mediated drug disposition (TMDD) model to characterize the substantial nonlinear PK of SPI-62. Objective The aim of the current analysis was to perform population PK/PD analysis to further link SPI-62 exposure (i.e., PK) with its response (i.e., inhibition of hepatic HSD-1 activity) to gain a quantitative understanding of the SPI-62 dose-exposure-response relationship. Methods PK and PD data from the first-in-human (FIH) clinical trials, including single ascending dose (SAD) and multiple ascending dose (MAD) studies, were used for model development. During the model development process, the final model selection was based on biological and physiological plausibility, goodness-of-fit plots, stability of parameter estimates, and objective function value. The nonlinear-mixed effect modeling (NONMEM) software was used for both the implementation of the PK/PD model and model simulation. SPI-62 plasma levels and hepatic HSD-1 inhibition over time following various dose regimens were simulated. Results The final model was a two-compartment TMDD model component for SPI-62 and an inhibitory I max model component for hepatic HSD-1 activity. The TMDD-hepatic PD model that we established adequately characterized all remarkable PK and PD behaviors of SPI-62, such as extremely low plasma exposures following the first low doses, nonlinear PK turned into linear PK after repeated low doses, and substantial and long-lasting hepatic HSD-1 inhibition following low doses. SPI-62 was estimated to bind to the target with a second-order association rate constant ( K on ) of 8.43 nM −1 h −1 and first-order dissociation rate constant ( K off ) value of 0.229 h −1 , indicating that SPI-62 binds rapidly to, and dissociates slowly from, its pharmacological target. The estimated target capacity ( R tot ) of 5460 nmol corresponds to approximately 2.2 mg of SPI-62, which comports well with the dose range in which PK nonlinearity is prominent. Model simulation results reveal that a 6 mg once-daily regimen can lead to long-lasting and substantial hepatic HSD-1 inhibition. Conclusions A population TMDD-PD model that explains SPI-62 nonlinear PK and hepatic HSD-1 inhibition following different dose regimens in healthy adults was successfully established. Our simulation results provide a solid foundation for model-informed development of SPI-62. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-0...

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

“…Furthermore, similar nonlinear PK profiles have been observed in other 11β‐HSD1 inhibitors, including ABT‐384, 24,25 SPI‐62, 26,27 MK‐0916, 28 and BMS‐823778 29 . Specifically, for ABT‐384, SPI‐62, and MK‐0916, TMDD models have been developed to explain their complex nonlinear PK in both single‐ and multiple‐dose regimens 24,26–28 . Taken together, this evidence strongly supports the presence of 11β‐HSD1‐mediated nonlinear PK in BI 187004.…”

“…BI 187004 exhibited remarkably similar nonlinear PK features to other 11β‐HSD1 inhibitors 23 . In previous studies, our group conducted a population TMDD model for ABT‐384 and both a population TMDD model and a population TMDD‐PKPD model for SPI‐62 24,26,27 . Despite their distinct chemical structures, the finalized TMDD models for both ABT‐384 and SPI‐62 are identical to the best model identified for BI 187004 in this study: a two‐compartment TMDD model with three transit absorption compartments.…”

“…The nonlinear characteristics observed in BI 187004 are consistent with typical PK and PD behaviors of small‐molecule compounds undergoing TMDD with targets located in tissues 20–23 . Furthermore, similar nonlinear PK profiles have been observed in other 11β‐HSD1 inhibitors, including ABT‐384, 24,25 SPI‐62, 26,27 MK‐0916, 28 and BMS‐823778 29 . Specifically, for ABT‐384, SPI‐62, and MK‐0916, TMDD models have been developed to explain their complex nonlinear PK in both single‐ and multiple‐dose regimens 24,26–28 .…”

“…To the best of our knowledge, four small‐molecule 11β‐HSD1 inhibitors have undergone model‐based population analysis: AMG‐221, 40 MK‐0916, 28 ABT‐384, 24 and SPI‐62 26,27 . AMG‐221's PK behavior was captured by a linear model, primarily due to only a slight lack of dose proportionality observed in plasma exposure at the study's lowest dose (3 mg) compared to higher doses.…”

“…The pharmacologic effects of other 11β‐HSD1 inhibitors, such as MK‐0916, ABT‐384, and SPI‐62, have been closely associated with the occupancy of its selective target 24,26–28 . Considering the shared mechanisms of action among 11β‐HSD1 inhibitors, we anticipated a straightforward relationship between hepatic target occupancy and BI 187004's hepatic 11β‐HSD1 inhibition.…”