osilodrostat has been researched along with Cushing-Syndrome* in 21 studies
9 review(s) available for osilodrostat and Cushing-Syndrome
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Osilodrostat for Cushing Disease and Its Role in Pediatrics.
Cushing disease (CD) is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of CD can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of CD are early or delayed puberty and hyperandrogenism in girls.. We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for CD, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population.. Osilodrostat is the first adrenal steroidogenesis inhibitor to be European Medicines Agency- and United States Food and Drug Administration-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary-free cortisol and a good safety profile. Osilodrostat's pharmacological properties and safety are currently being evaluated in a small Phase II trial (NCT03708900) - the first trial in the pediatric population (<18 years) with an estimated completion date in the year 2023. Topics: Adenoma; Adult; Child; Cushing Syndrome; Female; Humans; Hydrocortisone; Imidazoles; Pituitary ACTH Hypersecretion; Pituitary Neoplasms | 2023 |
Clinical Utility of Osilodrostat in Cushing's Disease: Review of Currently Available Literature.
Cushing's disease (CD) is caused by endogenous hypercortisolism as a result of adrenocorticotropin (ACTH) secretion from a pituitary tumor. The condition is associated with multiple comorbidities and increased mortality. First-line therapy for CD is pituitary surgery, performed by an experienced pituitary neurosurgeon. Hypercortisolism may often persist or recur after initial surgery. Patients with persistent or recurrent CD will generally benefit from medical therapy, often administered to patients who underwent radiation therapy to the sella and are awaiting its salutary effects. There are three groups of medications directed against CD, including pituitary-targeted medications that inhibit ACTH secretion from tumorous corticotroph cells, adrenally-directed medications that inhibit adrenal steroidogenesis and a glucocorticoid receptor (GR) antagonist. The focus of this review is osilodrostat, a steroidogenesis inhibitor. Osilodrostat (LCI699) was initially developed to lower serum aldosterone levels and control hypertension. However, it was soon realized that osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), leading to a reduction in serum cortisol levels. The focus of drug development then shifted from treatment of hypertension to treatment of hypercortisolism in CD. In a series of studies (LINC 1 through 4), osilodrostat was shown to be effective in normalizing 24-h urinary free cortisol (UFC) in the majority of treated patients and was approved for patients with CD who have failed surgery or are not surgical candidates. Further study is needed to examine the role of combination therapy as well as long-term outcomes of treated patients. Osilodrostat was shown to have an overall good safety profile. Most common adverse effects include nausea, headache, fatigue, arthralgias, dizziness, prolonged QT Topics: Adrenocorticotropic Hormone; Cushing Syndrome; Enzyme Inhibitors; Female; Humans; Hydrocortisone; Neoplasm Recurrence, Local; Pituitary ACTH Hypersecretion | 2023 |
Treatment of Cushing's syndrome with osilodrostat: practical applications of recent studies with case examples.
Endogenous Cushing's syndrome (CS) is a rare endocrine condition frequently caused by a tumor resulting in elevated cortisol levels. Cushing's disease (CD) caused by an adrenocorticotropic hormone-secreting pituitary adenoma is the most common form of endogenous CS. Medical therapy for CD is mostly used as second-line treatment after failed surgery or recurrence and comprises several pituitary-directed drugs, adrenal steroidogenesis inhibitors, and a glucocorticoid receptor blocker, some of which are US Food and Drug Administration (FDA)-approved for this condition. The recent Pituitary Society consensus guidelines for diagnosis and management of CD described osilodrostat, an oral inhibitor of 11β-hydroxylase, as an effective, FDA-approved medical therapy for CD. Because clinical experience outside clinical trials is limited, we provide here a review of published data about osilodrostat and offer example case studies demonstrating practical considerations on the use of this medication. Recommendations regarding osilodrostat are provided for the following situations: specific assessments needed before treatment initiation; monitoring for adrenal insufficiency, hypokalemia, and changes in QTc; the potential value of a slow up-titration in patients with mild disease; managing temporary treatment cessation for patients with CD who have acquired coronavirus disease 2019; monitoring for increased testosterone levels in women; exercising caution with concomitant medication use; considering whether a higher dose at nighttime might be beneficial; and managing cortisol excess in ectopic and adrenal CS. This review highlights key clinical situations that physicians may encounter when using osilodrostat and provides practical recommendations for optimal patient care when treating CS, with a focus on CD. Topics: Adenoma; COVID-19; Cushing Syndrome; Female; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; United States | 2022 |
Cushing's syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia.
Endogenous Cushing's syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment remains a challenge. In a long-term follow-up, biochemical control of hypercortisolemia, especially when severe, is difficult to achieve. Life-threatening hypercortisolemia is difficult to control due to the limitations of pharmacotherapy, including its side effects, and may require etomidate infusion in the intensive care unit (ICU) to rapidly lower cortisol levels. The effectiveness of hypercortisolemia management can be increased by a dual blockade of cortisol production. We report the efficacy, safety, and tolerability of combined therapy with two steroidogenesis inhibitors, etomidate, and osilodrostat, in a 32-year-old woman diagnosed with severe ACTH-dependent hypercortisolemia, subsequently maintaining a stable level of cortisol with osilodrostat monotherapy. This approach enabled achievement of relatively rapid control of the hypercortisolemia while using an etomidate infusion and concomitant increasing doses of oral osilodrostat applying a "titrations strategy." Our experience shows that it is worth taking advantage of the synergistic anticortisolic action of etomidate with osilodrostat. Topics: Adult; Cushing Syndrome; Etomidate; Female; Humans; Hydrocortisone; Imidazoles | 2022 |
Adrenally Directed Medical Therapies for Cushing Syndrome.
Endogenous Cushing syndrome (CS) is characterized by excess cortisol secretion, which is driven by tumorous secretion of corticotropin in the majority of patients. Untreated, CS results in substantial morbidity and mortality. Tumor-directed surgery is generally the first-line therapy for CS. However, hypercortisolism may persist or recur postoperatively; in other cases, the underlying tumor may not be resectable or its location may not be known. Yet other patients may be acutely ill and require stabilization before definitive surgery. In all these cases, additional interventions are needed, including adrenally directed medical therapies.. Electronic literature searches were performed to identify studies pertaining to adrenally acting agents used for CS. Data were abstracted and used to compile this review article.. Adrenally directed medical therapies inhibit one or several enzymes involved in adrenal steroidogenesis. Several adrenally acting medical therapies for CS are currently available, including ketoconazole, metyrapone, osilodrostat, mitotane, and etomidate. Additional agents are under investigation. Drugs differ with regards to details of their mechanism of action, time course of pharmacologic effect, safety and tolerability, potential for drug-drug interactions, and route of administration. All agents require careful dose titration and patient monitoring to ensure safety and effectiveness, while avoiding hypoadrenalism.. These medications have an important role in the management of CS, particularly among patients with persistent or recurrent hypercortisolism postoperatively or those who cannot undergo tumor-directed surgery. Use of these drugs mandates adequate patient instruction and close monitoring to ensure treatment goals are being met while untoward adverse effects are minimized. Topics: Adrenal Glands; Cushing Syndrome; Etomidate; Humans; Imidazoles; Ketoconazole; Metyrapone; Mitotane; Molecular Targeted Therapy; Pyridines | 2021 |
Updates in adrenal steroidogenesis inhibitors for Cushing's syndrome - A practical guide.
Medical therapy is essential in the management of patients with Cushing's syndrome (CS) when curative surgery has failed, surgery is not feasible, when awaiting radiation effect, and in recurrent cases of CS. Steroidogenesis inhibitors have a rapid onset of action and are effective in reducing hypercortisolism, however, adverse effects, including adrenal insufficiency require very close patient monitoring. Osilodrostat is the only steroidogenesis inhibitor to have been assessed in prospective randomized controlled trials and approved for Cushing's disease (CD) by the US Food and Drug Administration and for CS by the European Medical Agency (EMA). Osilodrostat has been shown to be highly effective at maintaining normal urinary free cortisol in patients with CD. Drugs such as metyrapone, ketoconazole (both EMA approved), and etomidate lack prospective evaluation(s). There is, however, considerable clinical experience and retrospective data that show a very wide efficacy range in treating patients with CS. In the absence of head-to-head comparative clinical trials, therapy choice is determined by the specific clinical setting, risk of adverse events, cost, availability, and other factors. In this review practical points to help clinicians who are managing patients with CS being treated with steroidogenesis inhibitors are presented. Topics: Cushing Syndrome; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Pituitary ACTH Hypersecretion; Practice Patterns, Physicians'; Pyridines; Steroids | 2021 |
Osilodrostat: First Approval.
Osilodrostat (Isturisa Topics: Administration, Oral; Cushing Syndrome; Drug Approval; Enzyme Inhibitors; Humans; Imidazoles; Molecular Conformation; Pyridines; Steroid 11-beta-Hydroxylase | 2020 |
Advances in the medical treatment of Cushing's syndrome.
Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome. Topics: ACTH Syndrome, Ectopic; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenal Gland Neoplasms; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cabergoline; Cushing Syndrome; Dopamine Agonists; ErbB Receptors; Gefitinib; Hormones; Humans; Imidazoles; Isoquinolines; Molecular Targeted Therapy; Pituitary ACTH Hypersecretion; Pyrazoles; Pyridines; Receptors, Glucocorticoid; Roscovitine; Somatostatin; Temozolomide; Tretinoin | 2019 |
Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing's syndrome.
Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice. Topics: Cushing Syndrome; Etomidate; Humans; Imidazoles; Ketoconazole; Metyrapone; Mitotane; Pyridines; Steroid Synthesis Inhibitors | 2015 |
1 trial(s) available for osilodrostat and Cushing-Syndrome
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A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing's syndrome other than Cushing's disease.
This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable. Topics: Adult; Aged; Cushing Syndrome; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Imidazoles; Japan; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pyridines; Treatment Outcome; Young Adult | 2020 |
11 other study(ies) available for osilodrostat and Cushing-Syndrome
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Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France.
Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS).. This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS.. A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11).. In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients.. Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect. Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Cushing Syndrome; Humans; Hydrocortisone; Prospective Studies; Retrospective Studies | 2023 |
LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome.
Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scarce for both molecules and a pharmacokinetically guided approach could help reaching eucortisolism more rapidly. We aimed to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ODT and MTP in human plasma. After addition of isotopically labeled internal standard (IS), plasma pretreatment consisted in protein precipitation with acetonitrile including 1% formic acid (v/v). Chromatographic separation was performed on Kinetex® HILIC (4.6 × 50 mm; 2.6 µm) analytical column with an isocratic elution during the 2.0-min run time. The method was linear from 0.5 to 250 ng/mL for ODT and from 2.5 to 1250 ng/mL for MTP. Intra- and inter-assay precisions were < 7.2%, with an accuracy ranging from 95.9% to 114.9%. The IS-normalized matrix effect ranged from 106.0% to 123.0% (ODT) and from 107.0% to 123.0% (MTP) and the range of the IS-normalized extraction recovery was 84.0-101.0% for ODT and 87.0-101.0% for MTP. The LC-MS/MS method was successfully applied in patients' plasma samples (n = 36), trough concentration of ODT and MTP ranged from 2.7 ng/mL to 8.2 ng/mL and from 10.8 ng/mL to 27.8 ng/mL, respectively. Incurred sample reanalysis exhibits less than 14% difference between the first and the second analysis for both drugs. This accurate and precise method, meeting all validation criteria, can therefore be used for plasma drug monitoring of ODT and MTP within the dose-titration period. Topics: Chromatography, Liquid; Cushing Syndrome; Humans; Metyrapone; Tandem Mass Spectrometry | 2023 |
Prolonged adrenocortical blockade following discontinuation of Osilodrostat.
Osilodrostat is the newest approved steroidogenic inhibitor drug for the treatment of hypercortisolism. In this article, we describe 3 patients who experienced a previously undescribed adverse event: a prolonged adrenocortical blockade following treatment cessation.. Patient records showing a history of successful hypercortisolism control with Osilodrostat followed by at least 4 weeks of treatment interruption were reviewed. Patient characteristics and hormonal dosage were analyzed.. Persistence of adrenocortical blockade was found in 3 patients and lasted from 6 weeks to 9 months depending on patients. This phenomenon manifested in patients regardless of lower or higher daily Osilodrostat doses (2-10 mg) and total treatment duration did not seem to predict the severity of the blockade.. The finding of this previously undescribed side effect highlights the importance of continuing adrenal function monitoring after Osilodrostat interruption to prevent adrenal crisis in patients at risk. Topics: Adrenal Insufficiency; Cushing Syndrome; Humans; Imidazoles; Pyridines | 2023 |
Pembrolizumab-induced cyclic ACTH-dependent Cushing's syndrome treated by a block-and-replace approach with osilodrostat.
Topics: Adrenocorticotropic Hormone; Antibodies, Monoclonal, Humanized; Cushing Syndrome; Humans; Imidazoles; Immune Checkpoint Inhibitors; Male; Middle Aged; Pyridines | 2022 |
Efficacy and tolerance of osilodrostat in patients with Cushing's syndrome due to adrenocortical carcinomas.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Aged, 80 and over; Cushing Syndrome; Female; Humans; Hydrocortisone; Imidazoles; Male; Middle Aged; Pyridines; Steroid 11-beta-Hydroxylase | 2022 |
Osilodrostat oral tablets for adults with Cushing's disease.
Endogenous Cushing's syndrome (CS) is a rare, multi-systemic condition resulting from chronic glucocorticoid excess sustained by a pituitary adenoma (Cushing's disease, CD), an adrenal adenoma or, less frequently, a neuroendocrine tumor. The optimal first-line option is surgery, but when it is contraindicated/refused, or in case of severe, life-threatening disease, medical treatment is a first-line choice. Osilodrostat (LCI699, Isturisa®) is a new, orally active adrenal steroidogenesis inhibitor currently approved by the FDA and EMA for the treatment of endogenous CS.. We illustrate the pharmacologic profile of osilodrostat and summarize the efficacy and safety of osilodrostat from the first phase I studies to the most recent evidence.. Osilodrostat acts as a potent, reversible inhibitor of 11β-hydroxylase (CYP11B1) and 18-hydroxylase (or aldosterone synthase, CYP11B2), counteracting both gluco- and mineralocorticoid production. According to the results of the LINC1, LINC2, and LINC3 studies and the preliminary findings of LINC4, osilodrostat offers an excellent efficacy in controlling hypercortisolism with a good tolerability. The non-negligible risk of adrenal insufficiency/steroid withdrawal symptoms, hypokalemia, and hyperandrogenism disorders, and the possibility, albeit rare, of pituitary tumor enlargement, require further confirmation and careful monitoring. Topics: Adult; Cushing Syndrome; Humans; Imidazoles; Mixed Function Oxygenases; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Pyridines; Tablets | 2022 |
Differences in the spectrum of steroidogenic enzyme inhibition between Osilodrostat and Metyrapone in ACTH-dependent Cushing syndrome patients.
Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS).. Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS).. Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2-688.4) and 14.9 (2.5-54.3) nmol/L, respectively) than in patients treated with Osilodrostat (10.3 (0.5-71.9) and 4.0 (0.3-13.3) nmol/L) (P = 0.0009 and P = 0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 (0.93-4.82) nmol/L vs 1.31(0.13-5.09) nmol/L, P = 0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were significantly decreased in Osilodrostat group (P < 0.0001).. In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat. Topics: Adrenocorticotropic Hormone; Androstenedione; Chromatography, Liquid; Cortodoxone; Cushing Syndrome; Female; Humans; Hydrocortisone; Imidazoles; Metyrapone; Pyridines; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase; Tandem Mass Spectrometry; Testosterone | 2022 |
Rapid control of severe ectopic Cushing's syndrome by oral osilodrostat monotherapy.
Topics: ACTH Syndrome, Ectopic; Cushing Syndrome; Cytochrome P-450 Enzyme Inhibitors; Female; Humans; Hydrocortisone; Imidazoles; Intensive Care Units; Middle Aged; Pyridines | 2021 |
Approach to the Patient Treated with Steroidogenesis Inhibitors.
Steroidogenesis inhibitors can be given to control the hypercortisolism of Cushing's syndrome in various situations: when surgery has been unsuccessful or not possible; in metastatic adrenocorticotropin hormone (ACTH) or cortisol-secreting tumors; when waiting for the maximal efficacy of radiation techniques; for rapid treatment of severe hypercortisolism in patients with occult ACTH-producing tumors; or as a presurgical treatment in patients with severe comorbidities. Whilst biochemical "control" can be achieved in more than 50% of cases, daily management of such drugs can be challenging. Indeed, with a "dose-titration" or a "block and replace" approach, defining eucortisolism is usually difficult, requiring the measurement of several biological markers. Moreover, each drug has its own side effects, which must be monitored closely. The aim of this "approach to the patient" is to shed light on the management of hypercortisolism with 4 steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat) to help endocrinologists dealing with patients with Cushing's syndrome. Various points will be discussed, such as initial dose of treatment, dose schedule, monitoring of efficacy, and side effects of monotherapy. The combination of steroidogenesis inhibitors will also be discussed. Topics: Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Enzyme Inhibitors; Female; Humans; Imidazoles; Ketoconazole; Metyrapone; Pyridines | 2021 |
Efficacy and tolerance of osilodrostat in patients with severe Cushing's syndrome due to non-pituitary cancers.
Topics: Adult; Aged; Cushing Syndrome; Female; Humans; Imidazoles; Male; Middle Aged; Neoplasms; Pyridines; Treatment Outcome | 2020 |
Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study.
Metyrapone and ketoconazole, frequently used steroidogenesis inhibitors for treatment of Cushing syndrome, can be associated with side effects and limited efficacy. Osilodrostat is a CYP11B1 and CYP11B2 inhibitor, with unknown effects on other steroidogenic enzymes.. To compare the effects of osilodrostat, metyrapone, and ketoconazole on adrenal steroidogenesis, and pituitary adenoma cells in vitro.. HAC15 cells, 17 primary human adrenocortical cell cultures, and pituitary adenoma cells were incubated with osilodrostat, metyrapone, or ketoconazole (0.01 to 10 µM). Cortisol and ACTH were measured using chemiluminescence immunoassays, and steroid profiles by liquid chromatography-mass spectrometry.. In HAC15 cells, osilodrostat inhibited cortisol production more potently (IC50: 0.035 µM) than metyrapone (0.068 µM; P < 0.0001), and ketoconazole (0.621 µM; P < 0.0001). IC50 values of osilodrostat and metyrapone for basal cortisol production varied with a 25- and 18-fold difference, respectively, with comparable potency. Aldosterone production was inhibited more potently by osilodrostat vs metyrapone and ketoconazole. Osilodrostat and metyrapone treatment resulted in strong inhibition of corticosterone and cortisol, 11-deoxycortisol accumulation, and modest effects on adrenal androgens. No pituitary-directed effects of osilodrostat were observed.. Under our study conditions, osilodrostat is a potent cortisol production inhibitor in human adrenocortical cells, comparable with metyrapone. All steroidogenesis inhibitors showed large variability in sensitivity between primary adrenocortical cultures. Osilodrostat might inhibit CYP11B1 and CYP11B2, in some conditions to a lesser extent CYP17A1 activity, and a proximal step in the steroidogenesis. Osilodrostat is a promising treatment option for Cushing syndrome, and in vivo differences with metyrapone are potentially driven by pharmacokinetic differences. Topics: Aldosterone; Cell Culture Techniques; Cortodoxone; Cushing Syndrome; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Pyridines; Steroid 11-beta-Hydroxylase | 2019 |