Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France

Jacques Young; Jérôme Bertherat; Marie Christine Vantyghem; Olivier Chabre; Salima Senoussi; Rita Chadarevian; Frédéric Castinetti; _ _; _ _; J Abeillon; C Ajzenberg; J-M Andrieu; A-S Arbey; F Archambeaud; G Arnault; J Bacchetta; E Baechler-Sadoul; F Bakiri; M Batisse-Lignier; C Baudry; E Benamo; A Bennet; A Berdelou; J Bertherat; A Boehna; F Borson-Chazot; N Bourcigaux; C Bourquard; L Bouys; C Bremont-Weill; L Bricaire; T Brue; D Buliga; P Cabaret; P Caron; M Cerro-Martinez; C Chambre; M Chardonnet; J Chatelin; C Clavel; C Coffin; R Cohen; C Collet-Gaudillat; C Cortet; A-L Coulon; F De Boisvilliers; A Decker-Bellaton; B Delemer; M De Menthon; V Degros; T Deneuville; R Desailloud; G Di Pietro; C Do Cao; B Donadille; M Dolz; P Dubray-Longeras; E Dutertre; H Du Rostu; J El Farkh; G Faure; P Finichel; N Gaits; F Galland; S Genc; E Ghanassia; J-J Girard; G Gravis; L Groza; F Grunenberger; C Guiheneuf; L Guignat; M Guigui; A Guilhem; M Joubert; C Jublanc; P Kamenicky; V Kerlan; Y Khalfallah; G Lambrey; E Landau; C Lautridou; H Lefebvre; M Le Bras; A-C Le Guillou; C Le Pommelet; F Léonard; L Lin; F Luca; C Lunogo; A Maisin; J-C Maiza; M Marty; P Meliani; S Menon; B Mestre; B Mignot; S Millot; I Morange; M Moret; N Morlet-Barla; H Narbonne; B Néraud; N Néri; P Niccoli; M L Nunes; S Oudard; S Papadopoulou; J-M Petit; G Petit-Aubert; A Perrin; M Philippon; C Pillegrand; L Potton; G Raverot; M L Rodes; Y Reznik; J L Sadoul; S Salenave; M Saraval-Gross; J Sarfati; J Savel; M A Schletzer; S Schneebeli; F Schillo; A Smagala; E Sonnet; R Teissier; M P Tessier; F Trulli; C Vackrine; D Vezzosi; A Viard; A Villeneuve; G Weryha; M Zalzali

doi:10.1530/eje-17-0886

Objective Ketoconazole (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. Design An observational prospective French cohort study (Compassionate Use Programme (CUP)). Methods Enrolled patients were stratified into a KTZ-naive cohort and a cohort already

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... ted 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. Results Overall, 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. Conclusions These 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.

doi:10.1530/eje-17-0886 pmid:29472378 fatcat:cdncux7tijdc5grurdiyakhajq

Citation

Jacques Young, Jérôme Bertherat, Marie Christine Vantyghem, Olivier Chabre, Salima Senoussi, Rita Chadarevian, Frédéric Castinetti, _ _, _ _, J Abeillon, C Ajzenberg, J-M Andrieu, A-S Arbey, F Archambeaud, G Arnault, J Bacchetta, E Baechler-Sadoul, F Bakiri, M Batisse-Lignier, C Baudry, E Benamo, A Bennet, A Berdelou, J Bertherat, A Boehna, F Borson-Chazot, N Bourcigaux, C Bourquard, L Bouys, C Bremont-Weill, L Bricaire, T Brue, D Buliga, P Cabaret, P Caron, M Cerro-Martinez, C Chambre, M Chardonnet, J Chatelin, C Clavel, C Coffin, R Cohen, C Collet-Gaudillat, C Cortet, A-L Coulon, F De Boisvilliers, A Decker-Bellaton, B Delemer, M De Menthon, V Degros, T Deneuville, R Desailloud, G Di Pietro, C Do Cao, B Donadille, M Dolz, P Dubray-Longeras, E Dutertre, H Du Rostu, J El Farkh, G Faure, P Finichel, N Gaits, F Galland, S Genc, E Ghanassia, J-J Girard, G Gravis, L Groza, F Grunenberger, C Guiheneuf, L Guignat, M Guigui, A Guilhem, M Joubert, C Jublanc, P Kamenicky, V Kerlan, Y Khalfallah, G Lambrey, E Landau, C Lautridou, H Lefebvre, M Le Bras, A-C Le Guillou, C Le Pommelet, F Léonard, L Lin, F Luca, C Lunogo, A Maisin, J-C Maiza, M Marty, P Meliani, S Menon, B Mestre, B Mignot, S Millot, I Morange, M Moret, N Morlet-Barla, H Narbonne, B Néraud, N Néri, P Niccoli, M L Nunes, S Oudard, S Papadopoulou, J-M Petit, G Petit-Aubert, A Perrin, M Philippon, C Pillegrand, L Potton, G Raverot, M L Rodes, Y Reznik, J L Sadoul, S Salenave, M Saraval-Gross, J Sarfati, J Savel, M A Schletzer, S Schneebeli, F Schillo, A Smagala, E Sonnet, R Teissier, M P Tessier, F Trulli, C Vackrine, D Vezzosi, A Viard, A Villeneuve, G Weryha, M Zalzali. "Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France." European Journal of Endocrinology 178.5 (2018) 447-458

Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France

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