EYES2023 Poster Presentations Guided Poster Tour 1: Adrenal and Neuroendocrine tumors (10 abstracts)
Decrease in anticortisolic drug osilodrostat plasma exposure in patients treated with mitotane for an adrenocortical carcinoma
Louis Thomeret 1 , Alicja Puszkiel 2 , David Balakirouchenane 2 , Lucas Bouys 3 , Jonathan Poirier 4 , Annabel Berthon 1 , Bruno Ragazzon 1 , Anne Jouinot 1 , Laurence Guignat 4 , Laura Bessiene 4 , Rossella Libe 4 , Leopoldine Bricaire 4 , Lionel Groussin 3 , Guillaume Assie 3 , Benoit Blanchet 2 , Fideline Bonnet-Serrano 5 & Jerome Bertherat 3
1Institut Cochin, Team ‘Genomic and Signaling of Endocrine Tumors’, Inserm U1016-Cnrs Umr8104, Paris, France; 2Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, Ap-Hp, Paris, France; 3Endocrinology Department, Reference Center for Rare Adrenal Disorders, Cochin Hospital, Ap-Hp, Institut Cochin, Team ‘Genomic and Signaling of Endocrine Tumors’, Inserm U1016-Cnrs Umr8104, Paris, France; 4Endocrinology Department, Reference Center for Rare Adrenal Disorders, Cochin Hospital, Ap-Hp, Paris, France; 5Hormonology Department, Cochin Hospital, Ap-Hp, Institut Cochin, Team ‘Genomic and Signaling of Endocrine Tumors’, Inserm U1016-Cnrs Umr8104, 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). Plasma exposure may contribute to this variability. Our objective was to investigate the effect of concomitant use of mitotane (MIT), a potent inducer of CYP450 (3A4), on circulating OSI concentrations in patients treated for an adrenocortical carcinoma (ACC).
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 27 patients (19 with Cushing’s disease, 4 with ectopic adrenocorticotropic secretion, 3 with macronodular bilateral adrenal hyperplasia and 1 with ACC) treated with OSI as a monotherapy (‘OSI’ group, 33 cycles), and in 3 patients treated with OSI in association with MIT (‘OSI-MIT’ group, 8 cycles) for ACC. OSI was administered twice daily. Daily doses of OSI and plasma levels of MIT were expressed as median (min-max). The area under the OSI concentration curve (AUC-OSI) was used as pharmacokinetic endpoint.
Results: The AUC-OSI was well correlated with the daily dose of osilodrostat in both the ‘OSI’ group (Spearman r=0.83462; OSI 10 mg/day (2–40)) and the ‘OSI-MIT’ group with plasma MIT level > 10 mg/l (Spearman r=0.9487; OSI 50 mg/day (20–60); plasma MIT level 19.1 mg/l (13.5–26.6)). Normalized to the daily dose, the AUC-OSI was statistically decreased in the ‘OSI-MIT’ group compared to the ‘OSI’ group (medians: 14.10 vs 27.10 ng/ml.h; P<0.001), as well as the residual concentration (P=0.003). In a single patient, higher plasma MIT level seemed associated with higher reduction in OSI plasma exposure.
Discussion: Mitotane significantly decreases plasma exposure to osilodrostat in patients treated for a cortisol-secreting ACC. Monitoring plasma levels of osilodrostat could thus be particularly useful for therapeutic adaptation in these patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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