osilodrostat
Regulatory sources consulted
Approved indications
- Treatment of endogenous Cushing syndrome in adults.
Contraindications
Absolute
- Hypersensitivity to osilodrostat or excipients.
Clinical warnings
- Major warning · It may cause hypocortisolism and adrenal insufficiency at any time and after discontinuation. Monitor cortisol; reduce, interrupt, and treat with glucocorticoid when appropriate. — CIMA/AEMPS, ficha técnica 1191407001
- Major warning · It prolongs QT in a dose-dependent manner. Obtain an ECG before starting, after one week, and then as indicated; correct hypokalemia, hypocalcemia, and hypomagnesemia and monitor electrolytes. — CIMA/AEMPS, ficha técnica 1191407001
- Major warning · Adrenal precursor accumulation may cause hypertension, hypokalemia, edema, hirsutism, or acne; monitor blood pressure, potassium, and clinical signs. — CIMA/AEMPS, ficha técnica 1191407001
Drug interactions
- HighQT-prolonging drugs
Mechanism: The pharmacodynamic effect may be additive and increase arrhythmia risk.
Recommendation: Avoid when possible; if necessary, monitor ECG and electrolytes closely.
CIMA/AEMPS, ficha técnica 1191407001
- HighSensitive CYP1A2, CYP2C19, CYP2D6, or CYP3A4 substrates
Mechanism: Osilodrostat inhibits these enzymes and may increase substrate exposure, especially for narrow-therapeutic-index drugs.
Recommendation: Monitor toxicity and adjust the substrate according to its label.
CIMA/AEMPS, ficha técnica 1191407001
Adverse events
Common (≥1%)
Adrenal insufficiency, hypokalemia, headache, dizziness, nausea, vomiting, diarrhea, abdominal pain, fatigue, and edema
Rare but serious
Adrenal crisis, syncope, and arrhythmia associated with QT prolongation
Pregnancy and lactation
It may cause fetal harm. Perform a pregnancy test before starting and use effective contraception during treatment and for one week afterward. Do not use in women of childbearing potential without contraception; breastfeeding is not recommended during treatment and for one week afterward.
Recent literature (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.