ECE2024 Rapid Communications Rapid Communications 7: Endocrine-related Cancer (6 abstracts)
Decrease in anticortisolic drmg osilodrostat plasma exposure in patients treated with mitotane for adrenocortical carcinoma
Louis Thomeret 1 , Alicja Puszkiel 2 , David Balakirouchenane 2 , Lucas Bouys 1,3 , Jonathan Poirier 3 , Annabel Berthon 1 , Bruno Ragazzon 1 , Anne Jouinot 1 , Laurence Guignat 3 , Laura Bessiene 3 , Rossella Libe 3 , Léopoldine Bricaire 3 , Marie-Clémence Leguy 4 , Jean Guibourdenche 4 , Lionel Groussin-Rouiller 1,3 , Guillaume Assie 1,3 , Benoît Blanchet 2 , Jérôme Bertherat 1,3 & Fidéline Bonnet-Serrano 1,4
1Institut Cochin, INSERM U1016 - CNRS UMR8104, Université Paris-Cité, Team "Genomics and signaling of Endocrine Tumors", PARIS, France; 2Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Department of Pharmacokinetics and Pharmacochemistry, PARIS, France; 3Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Endocrinology department, PARIS, France; 4Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Hormonology department, PARIS, France
Introduction: The steroidogenesis inhibitor osilodrostat (OSI), indicated for the medical treatment of endogenous Cushing’s syndrome, exhibits significant interindividual variability regarding the response to treatment (Pivonello et al., 2020), a fortiori in the context of adrenocortical carcinoma (Tabarin et al., 2022). Plasma exposure may contribute to this variability. Our objective was to investigate the effect of concomitant use of mitotane (MITO), a potent inducer of CYP450 (3A4), on circulating OSI concentrations in patients treated for an adrenocortical carcinoma (ACC).
Materials and Methods: Plasma OSI concentrations were determined every 4 hours over 24 hours (sampling at 8 h, 12 h, 16 h, 20 h, 24 h and 4 h) by LC-MS/MS (Balakirouchenane et al., 2023) in 29 patients treated for different etiologies of endogenous Cushing’s syndrome: Cushing’s disease (n=19), ectopic Cushing’s syndrome (n=4), primary bilateral macronodular adrenal disease (n=3) and adrenocortical carcinoma (n=3). Twenty-seven patients were treated with OSI as a monotherapy (“OSI” group, 33 cycles) and 3 patients were treated ith OSI in association with MITO ("OSI-MITO" group, 8 cycles) for an ACC. OSI was administered twice daily in all patients. Daily doses of OSI and plasma MITO concentrations were expressed as median [min-max].
Results: Even after a long period of treatment (> 6 months), high fluctuations of OSI concentrations were observed along the day (median CV = 55%). The area under the OSI concentration curve (AUC-OSI) was thus used as pharmacokinetic endpoint. The AUC-OSI was well correlated with the daily dose of osilodrostat in both the "OSI" group (Spearman r0.84; OSI 10 [2-40] mg/day) and the "OSI-MITO" group (Spearman r0.85; OSI 60 [20-60] mg/day; plasma MITO concentration 14.1 [0.5-26.6] mg/l). However, the slope of the linear regression line was lower in “OSI-MITO” group. The AUC-OSI based on the daily dose was also statistically decreased in the "OSI-MITO" group compared to the "OSI" group (medians: 11.92 vs 26.81 ng/ml.h; P<0.001).
Discussion: Mitotane significantly decreases plasma exposure to Osilodrostat in patients treated for a cortisol-secreting ACC. This is likely explained by the induction of CYP450 by Mitotane and should be taken in account to adjust the Osilodrostat dose in patients treated with Mitotane.References1. Pivonello et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase, The lancet. Diabetes & endocrinology, 2020.2. Tabarin et al. Efficacy and tolerance of osilodrostat in patients with Cushing's syndrome due to adrenocortical carcinomas, European Journal of Endocrinology, 2022.3. Balakirouchenane et al. LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing’s Syndrome, Journal of pharmaceutical and biomedical analysis, 2023.
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Endocrine Abstracts
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