Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France
Author:
Young Jacques123, Bertherat Jérôme4, Vantyghem Marie Christine5, Chabre Olivier678, Senoussi Salima9, Chadarevian Rita910, Castinetti Frédéric11, _ _, _ _, Abeillon J, Ajzenberg C, Andrieu J-M, Arbey A-S, Archambeaud F, Arnault G, Bacchetta J, Baechler-Sadoul E, Bakiri F, Batisse-Lignier M, Baudry C, Benamo E, Bennet A, Berdelou A, Bertherat J, Boehna A, Borson-Chazot F, Bourcigaux N, Bourquard C, Bouys L, Bremont-Weill C, Bricaire L, Brue T, Buliga D, Cabaret P, Caron P, Cerro-Martinez M, Chambre C, Chardonnet M, Chatelin J, Clavel C, Coffin C, Cohen R, Collet-Gaudillat C, Cortet C, Coulon A-L, De Boisvilliers F, Decker-Bellaton A, Delemer B, De Menthon M, Degros V, Deneuville T, Desailloud R, Di Pietro G, Do Cao C, Donadille B, Dolz M, Dubray-Longeras P, Dutertre E, Du Rostu H, El Farkh J, Faure G, Finichel P, Gaits N, Galland F, Genc S, Ghanassia E, Girard J-J, Gravis G, Groza L, Grunenberger F, Guiheneuf C, Guignat L, Guigui M, Guilhem A, Joubert M, Jublanc C, Kamenicky P, Kerlan V, Khalfallah Y, Lambrey G, Landau E, Lautridou C, Lefebvre H, Le Bras M, Le Guillou A-C, Le Pommelet C, Léonard F, Lin L, Luca F, Lunogo C, Maisin A, Maiza J-C, Marty M, Meliani P, Menon S, Mestre B, Mignot B, Millot S, Morange I, Moret M, Morlet-Barla N, Narbonne H, Néraud B, Néri N, Niccoli P, Nunes M L, Oudard S, Papadopoulou S, Petit J-M, Petit-Aubert G, Perrin A, Philippon M, Pillegrand C, Potton L, Raverot G, Rodes M L, Reznik Y, Sadoul J L, Salenave S, Saraval-Gross M, Sarfati J, Savel J, Schletzer M A, Schneebeli S, Schillo F, Smagala A, Sonnet E, Teissier R, Tessier M P, Trulli F, Vackrine C, Vezzosi D, Viard A, Villeneuve A, Weryha G, Zalzali M
Affiliation:
1. 1Univ Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin Bicetre, France 2. 2Service d’Endocrinologie et des Maladies de la Reproduction, Assistance Publique–Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicetre, France 3. 3INSERM U1185, Le Kremlin-Bicetre, France 4. 4Department of Endocrinology, Metabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, Paris, France 5. 5Service d’Endocrinologie et Maladies Métaboliques, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, INSERM U1190, EGID, Lille, France 6. 6Service d’Endocrinologie-Diabétologie-Nutrition, CHU Grenoble-Alpes, Grenoble, France 7. 7Faculté de Médecine Université Grenoble-Alpes, Grenoble, France 8. 8INSERM U 1036, iRTSV-BCI, CEA-Grenoble, Grenoble, France 9. 9HRA France, Paris, France 10. 10Service d’endocrinologie-métabolisme, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France 11. 11Department of Endocrinology, Aix Marseille Universite, CNRS UMR7286, Assistance Publique-Hopitaux de Marseille, La Conception Hospital, Marseille, France
Abstract
ObjectiveKetoconazole (KTZ) is one of few available treatments for Cushing’s syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ.DesignAn observational prospective French cohort study (Compassionate Use Programme (CUP)).MethodsEnrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury.ResultsOverall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes.ConclusionsThese findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism
Cited by
52 articles.
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