Post-authorisation safety study of ketoconazole HRA in endogenous cushing

Frederic Castinetti; Webb Susan M; Alicia Santos; Jerome Bertherat; Filippo Ceccato; Tomsic Karin Zibar; Claudia Amaral; Richard Feelders; Alexis Rames; Nader Myriam Bou; Thierry Brue; Maso Anna Aulinas

doi:10.1530/endoabs.110.P782

P782

Prev Next

Section Contents Cite

Endocrine Abstracts (2025) 110 P782 | DOI: 10.1530/endoabs.110.P782

ECEESPE2025 Poster Presentations Multisystem Endocrine Disorders (43 abstracts)

Post-authorisation safety study of ketoconazole HRA in endogenous cushing’s syndrome: seventh annual interim report in 108 patients

Frederic Castinetti ¹ , Susan M Webb ² , Alicia Santos ² , Jérôme Bertherat ³ , Filippo Ceccato ⁴ , Karin Zibar Tomsic ⁵ , Claudia Amaral ⁶ , Richard Feelders ⁷ , Alexis Rames ⁸ , Myriam Bou Nader ⁸ , Thierry Brue ¹ & Anna Aulinas Maso ²

Author affiliations

¹Hôpital de la Conception, Department of Endocrinology, Marseille, France; ²Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Department of Endocrinology, CIBERER Unit 747, UAB, Barcelona, Spain; ³Hôpital Cochin, Department of Endocrinology, Paris, France; ⁴University Hospital of Padova, Department of Endocrinology, Padova, Italy; ⁵University Hospital Zagreb, Department of Endocrinology, Zagreb, Croatia; ⁶Centro Hospitalar Universitário do Santo António, Department of Endocrinology, Porto, Portugal; ⁷Erasmus University Medical Center Rotterdam, Department of Endocrinology, Rotterdam, Netherlands; ⁸Esteve RD France, Montrouge, France

JOINT36

Background: Ketoconazole HRA is approved for the treatment of endogenous Cushing’s Syndrome (CS) pursuant to an obligation to collect safety data on patients exposed to the drug in this indication.

Methods: The primary objective of this open-label post-authorisation safety study (PASS), using the European Registry on Cushing’s Syndrome (ERCUSYN), is to document liver and cardiac tolerability. Treatment pattern, overall safety, and effectiveness are secondary objectives. The last interim report is presented.

Results: At the cut-off date (31 August 2024), 110 patients were enrolled in the study. One hundred and eight patients were included in the full analysis set, 103 were evaluated for safety, and 105 for efficacy. Mean age of the patients was 46.8 years, and most patients (77.4%) were diagnosed with pituitary-dependent CS. Ketoconazole HRA was mainly used as monotherapy in 85.2% (92/108) of patients, with a median exposure of 1.6 years and a mean average daily dose of 400 mg. Among 41 cases of liver functions test (LFT) abnormalities, occurring mostly within the first month, in 22 cases LFT were < 2 x ULN and resolved without discontinuation of Ketoconazole HRA. Eight cases (7.4%) of hepatotoxicity (LFT > 5 x ULN) were observed. Co-administration of a known hepatotoxic drug was suspected in 6 of these patients. In all 8 patients, liver injury resolved after discontinuation of ketoconazole HRA, 5 of these events were hepatocellular. No QTc prolongation cases were reported. However, ECG and LFT monitoring remain non-systematic. Overall, 51.9% of patients (56/108) experienced at least one adverse event (AE). Thirty-five patients (32.4%) experienced at least one AE other than LFT abnormalities and QTc prolongation. Non-serious AEs were mainly gastrointestinal disorders (13.6%), nausea being the most frequent of them (12.6%). The rate of serious AEs, other than LFT abnormalities and QTc prolongation, was 11.7%, of which 3.9% were endocrine disorders, mainly acute adrenocortical insufficiency (1.9%). Efficacy data showed that 50.8% of patients achieved normalized UFC levels, while 60.5% attained normalized morning plasma cortisol levels.

Conclusion: These results confirm the known safety and efficacy profile of Ketoconazole HRA. No unexpected safety signals were identified. In addition, the benefit-risk balance of Ketoconazole HRA in patients with endogenous Cushing’s syndrome remains favourable.