A preliminary model to tailor osilodrostat in patients with ACTH-dependent Cushing’s syndrome

Over the past 10 years, osilodrostat has become one of the most commonly used steroidogenesis inhibitors in Cushing's syndrome. The starting dose is usually determined based on the product characteristics, the prescriber's experience, and cortisol levels. However, no study has attempted to determine whether there was a dose-response relationship between osilodrostat and cortisol reduction. In this study, we developed a preliminary kinetic-pharmacodynamic model to tailor osilodrostat in patients with ACTH dependent Cushing's syndrome. We first analyzed the decrease in cortisol 48 hours after initiation or dose change of osilodrostat in 18 patients. Simulations were then performed for different doses of osilodrostat to evaluate the variation in cortisol concentrations. Our results report the first dose-response relationship between osilodrostat dose and cortisol levels, which should be helpful in identifying the optimal dosing regimen in patients with Cushing's syndrome and in individualizing treatment to approximate a nychthemeral rhythm.