osilodrostat
Sources réglementaires consultées
Indications approuvées
- Traitement du syndrome de Cushing endogène chez l’adulte.
Contre-indications
Absolues
- Hypersensibilité à l’osilodrostat ou aux excipients.
Mises en garde cliniques
- Mise en garde majeure · Il peut provoquer un hypocortisolisme et une insuffisance surrénalienne à tout moment et après l’arrêt. Surveiller le cortisol ; réduire, interrompre et traiter par glucocorticoïde si nécessaire. — CIMA/AEMPS, ficha técnica 1191407001
- Mise en garde majeure · Il allonge le QT de façon dose-dépendante. Réaliser un ECG avant le traitement, après une semaine puis selon l’indication ; corriger l’hypokaliémie, l’hypocalcémie et l’hypomagnésémie et surveiller les électrolytes. — CIMA/AEMPS, ficha técnica 1191407001
- Mise en garde majeure · L’accumulation de précurseurs surrénaliens peut provoquer hypertension, hypokaliémie, œdème, hirsutisme ou acné ; surveiller la pression artérielle, le potassium et les signes cliniques. — CIMA/AEMPS, ficha técnica 1191407001
Interactions médicamenteuses
- SévèreMédicaments allongeant le QT
Mécanisme: L’effet pharmacodynamique peut être additif et augmenter le risque d’arythmie.
Recommandation: Éviter si possible ; si nécessaire, surveiller étroitement l’ECG et les électrolytes.
CIMA/AEMPS, ficha técnica 1191407001
- SévèreSubstrats sensibles des CYP1A2, CYP2C19, CYP2D6 ou CYP3A4
Mécanisme: L’osilodrostat inhibe ces enzymes et peut augmenter l’exposition aux substrats, surtout ceux à marge thérapeutique étroite.
Recommandation: Surveiller la toxicité et ajuster le substrat selon son RCP.
CIMA/AEMPS, ficha técnica 1191407001
Effets indésirables
Communs (≥1%)
Insuffisance surrénalienne, hypokaliémie, céphalée, vertiges, nausées, vomissements, diarrhée, douleur abdominale, fatigue et œdème
Rares mais graves
Crise surrénalienne, syncope et arythmie associée à un allongement du QT
Grossesse et allaitement
Il peut provoquer des lésions fœtales. Réaliser un test de grossesse avant le traitement et utiliser une contraception efficace pendant le traitement et pendant une semaine après. Ne pas utiliser chez les femmes en âge de procréer sans contraception ; l’allaitement n’est pas recommandé pendant le traitement ni pendant la semaine qui suit.
Bibliographie récente (PubMed)
Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat). Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable. Osilodrostat is an inhibitor of cortisol synthesis that is used in the treatment of Cushing disease not controlled by standard therapy. Osilodrostat therapy has not been linked to serum aminotransferase elevations during therapy or with instances of clinically app
Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.
Medical treatment of hypercortisolism may be necessary for a high proportion of patients with Cushing syndrome (CS), including those who are not candidates for curative surgery. It may also be used in the presurgical period when hypercortisolism is severe, as long-term treatment following surgical failure or recurrence after surgery, or while waiting for the effects of pituitary radiation in Cushing disease. Currently available medical treatments include adrenal steroidogenesis inhibitors that block cortisol secretion (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate), drugs that modulate pituitary ACTH secretion (pasireotide and cabergoline), and drugs that block peripheral glucocorticoid receptors (mifepristone). In addition, there are other medical treatments in development that target pituitary signaling pathways, ACTH or its adrenal receptor, or the conversion of cortisol from cortisone by 11ßHSD1. Steroidogenesis inhibitors can be administered using either a titration or a block-and-replace approach. Titration requires adjusting the daily drug dose with the aim of normalizing circulating cortisol levels, whereas the block-and-replace strategy uses higher drug doses to fully suppress endogenous cortisol production, followed by glucocorticoid supplementation. In this review, we summarize the main indications for medical treatment in CS, the mechanism of drug action, efficacy, recommended doses, and safety of the currently available drugs, as well as potential future treatments. We also discuss titration and block-and-replace approaches for control of hypercortisolism and provide recommendations for the use and monitoring of medical treatment in CS, including patients with endogenous hypercortisolism in special situations such as pregnancy, cyclic CS, and mild autonomous cortisol secretion.
Excess aldosterone production contributes to the development of hypertension and results in fibrosis with dysfunction of the heart, vasculature and kidneys. Consequently, new agents have been developed to reduce endogenous aldosterone synthesis. The primary objective of this systematic review is to describe the BP-lowering effects of aldosterone synthase inhibitors (ASIs) in hypertensive patients and, secondly, to describe their potential renal protective effects and possible influence on cortisol production and plasma potassium. We searched PubMed, Embase and ClinicalTrials.gov and included randomized controlled and clinical trials according to PICO using the review tool Covidence. Thirteen studies were included and all demonstrated BP reduction through ASI treatment. Among patients with apparent resistant hypertension, the placebo-corrected reductions in seated systolic BP were 11.0 mmHg for baxdrostat and 9.6 mmHg for lorundrostat. A significant suppression of cortisol production was found for LCI699 (osilodrostat) but not for baxdrostat, lorundrostat, BI 690517 (vicadrostat) or dexfadrostat. Studies on BI 690517 showed a reduction in urine-albumin-creatinine ratio, indicating renal protection. ASIs may increase potassium levels. We conclude that ASIs have promising BP-lowering effects with very limited effects on cortisol production and offer reno-protective effects in chronic kidney disease. Studies on hypertensive target organ damage and cardiovascular outcomes are, however, lacking.