Introduction: Osilodrostat is a new 11 ß-hydroxylase inhibitor with a mode of action analogue to metyrapone. It has become increasingly used in recent years for treatment of Cushings Syndrome (CS). However, few in vivo studies are currently available to accurately compare both drugs characteristics. The objective of our study was to compare steroidogenic profiles in patients treated by either Osilodrostat or Metyrapone for ACTH-dependent CS.
Methods: Patients followed in Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone were included. A serum profile of 5 steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined in high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).
Results: Twenty-five patients treated by Osilodrostat and 14 patients treated by Metyrapone were thus included. Cortisol level was lower in Osilodrostat group (175 [22-421] nmol/l) in comparison to Metyrapone group (307 [68-547] nmol/), P=0.025; hypocortisolism (basal 8:00 AM cortisol < 100 nmol/l) being found in 48% of patients treated by Osilodrostat and 7% of patients treated by Metyrapone. 11-deoxycortisol level was higher in patients treated by Metyrapone (80.9 [2.2-688.4] nmol/l) than in patients treated by Osilodrostat (10.3 [0.5-71.9] nmol/l), P=0.0009. Similarly, androstenedione level was higher in Metyrapone group (14.9 [2.5-54.3] nmol/l) than in Osilodrostat group (4.0 [0.3-13.3] nmol/l), P=0.0005. Testosterone level in women patients was also higher in Metyrapone group (3.3 [0.93-4.82] nmol/l) than in Osilodrostat group (1.31[0.13-5.09] nmol/l), P=0.0146. Steroidogenic enzymes activity was evaluated by upstream/downstream steroids ratio, a higher ratio thus reflecting an accumulation of the enzyme substrate, i.e a lower enzymatic activity. CYP11B1 activity, evaluated by 11-deoxycortisol/cortisol ratio, was not different between Metyrapone group (22.4 [0.7-410]) and Osilodrostat group (7.53 [1.0-47.3]), P=0.1254. CYP21A2 activity, assessed by 17OHprogesterone/11-deoxycortisol ratio, was significantly decreased in Osilodrostat group (18.6 [4.89-101.9]) in comparison to Metyrapone group (3.1[1.3-31.8]), P<0.0001, as well as CYP17A1 activity, evaluated by 17OHprogesterone/androstenedione ratio: 56.9 [17.7-136.5] in Osilodrostat group in comparison to 18.3 [5.8-46.8] in Metyrapone group, P<0.0001.
Conclusion: In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in standard routine care suggest that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and in androgens levels in patients treated by Osilodrostat and should be taken in consideration for patients management.
21 May 2022 - 24 May 2022