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

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. 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. 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.