OC35 - Fluctuations in diurnal plasma cortisol cycle in patients treated with metyrapone or osilodrostat for endogenous Cushing syndrome

Background Steroidogenesis inhibitors represent an efficient pharmacological option in the treatment of endogenous Cushing Syndrome (CS). Metyrapone and Osilodrostat are both 11 beta-hydroxylase inhibitors but impact differently global steroidogenic profile according to previous clinical and in vitro studies. Purpose The aim of our work was to investigate diurnal fluctuations of plasma steroids concentrations in patients treated by either Metyrapone or Osilodrostat. Methods Plasma steroids and drug concentrations diurnal profiles (6 samples a day) were determined using UPLC-tandem mass spectrometry (UPLC-MS/MS) for patients treated with Metyrapone (n=14; median posology 1250 mg/day; median treatment duration 246 days) or Osilodrostat (n=21; 10 mg/day; 242 days) for various causes of CS, as well as in 14 non-treated patients with CS and 16 controls. Plasma profile of 14 steroids included cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, progesterone, cortisone, 21-deoxycortisol, androstenedione, testosterone, as well as 3 mineralocorticoids and 3 11-oxygenated androgens. Concentrations fluctuations in a 24-hour cycle were expressed by MIN-MAX range (MMR) and Coefficient of Variation (CV, %) (median [10-90 percentiles]). Results Cortisol plasma levels were significantly more stable during 24-hour cycle in patients treated with Osilodrostat than Metyrapone (MMR=100.9 nmol/L [7.3-283.8] vs 291.7 [122.5-482.6], p=0.0002). This difference was observed whatever hypercortisolism was strongly controlled (normal Urinary Free Cortisol + late-night plasma cortisol < 100 nmol/L) or not. 11-deoxycortisol plasma fluctuations were also higher in Metyrapone cycles compared to Osilodrostat (MMR=78.2 nmol/L [24.0-327.8] vs 14.5 [0.5-77.8], p<0.0001), and compared to normal cycles and non-treated cycles. In our cohort, Osilodrostat plasma 24-hour concentrations were also more stable than Metyrapone concentrations (CV 51.2% [34.6-107.6] vs. 123.0% [53.8-191.4], p=0.0002). Conclusion Our results show a higher stability in plasma cortisol levels in patients treated by Osilodrostat compared to Metyrapone, as well as for 11-deoxycortisol. These observations could result from differences in pharmacokinetics between the two drugs. An insight into other steroids (precursors and androgens) concentrations and analyses of correlations with pharmacodynamic parameters has also been performed to have an in vivo overview of the pharmacological impact of Metyrapone and Osilodrostat on the whole steroidogenesis.