Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

References

• Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Pituitary. 2016 Dec; 19(6):643–653.
   PubMed Web of Science ®Google Scholar
• Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf). 1994 Apr; 40(4):479–484.
   PubMed Web of Science ®Google Scholar
• Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001 Jan;86(1)117–123.
   PubMed Web of Science ®Google Scholar
• Dekkers OM, Horváth-Puhó E, Jørgensen JO, et al. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. J Clin Endocrinol Metab. 2013 Jun;98(6)2277–2284.
   PubMed Web of Science ®Google Scholar
• Wengander S, Trimpou P, Papakokkinou E, et al. The incidence of endogenous Cushing's syndrome in the modern era. Clin Endocrinol (Oxf). 2019 Aug;91(2)263–270.
   PubMed Web of Science ®Google Scholar
• Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012 Mar-Apr; 25(2):199–208.
   PubMed Web of Science ®Google Scholar
• Clayton RN, Jones PW, Reulen RC, et al. Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol. 2016 Jul;4(7)569–576.
   PubMed Web of Science ®Google Scholar
• Van Haalen FM, Broersen LH, Jorgensen JO, et al. Mortality remains increased in Cushing's disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol. 2015 Apr;172(4)R143–R149.
   PubMed Web of Science ®Google Scholar
• Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016 Jul;4(7)611–629.
   PubMed Web of Science ®Google Scholar
• Pivonello R, Simeoli C, De Martino MC, et al. Neuropsychiatric disorders in Cushing's syndrome. Front Neurosci. 2015;9:129.
   PubMed Web of Science ®Google Scholar
• Santos A, Resmini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing's syndrome: prevalence, diagnosis and management. Drugs. 2017 May;77(8)829–842.
   PubMed Web of Science ®Google Scholar
• Lacroix A, Feelders RA, Stratakis CA, et al. Cushing's syndrome. Lancet. 2015 Aug 29;386(9996)913–927.
   PubMed Web of Science ®Google Scholar
• Sharma ST, Nieman LK, Feelders RA, et al. Cushing's syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–293.
   PubMed Web of Science ®Google Scholar
• Turcu AF, Auchus RJ. Mild adrenal cortsol excess. In: Geer EB, editor. The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease: Cushing's Syndrome and Beyond. Cham, Switzerland: Springer Nature; 2017. p. 181–197.
   Google Scholar
• Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: european society of endocrinology clinical practice guideline in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2016 Aug;175(2)G1–G34.
   PubMed Web of Science ®Google Scholar
• Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807–2831.
   PubMed Web of Science ®Google Scholar
• Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing's disease. Endocr Rev. 2015 Aug;36(4):385–486.
   PubMed Web of Science ®Google Scholar
• Hinojosa‑Amaya JM, Cuevas‑Ramos D, Fleseriu M, et al. Medical management of Cushing's syndrome: current and emerging treatments. Drugs. 2019;79(9):935–956.
   PubMed Web of Science ®Google Scholar
• Castinetti F, Brue T, Ragnarsson O, et al. Radiotherapy as a tool for the treatment of Cushing's disease. Eur J Endocrinol. 2019 May 1;180(5)D9–D18.
   PubMed Web of Science ®Google Scholar
• Reincke M, Ritzel K, Osswald A, et al. A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome. Eur J Endocrinol. 2015 Oct;173(4)M23–M32.
   PubMed Web of Science ®Google Scholar
• Rubinstein G, Osswald A, Zopp S, et al. Therapeutic options after surgical failure in Cushing's disease: a critical review. Best Pract Res Clin Endocrinol Metab. 2019 Apr;33(2)101270.
   PubMed Web of Science ®Google Scholar
• Tritos NA, Biller BM. Medical therapy for Cushing's syndrome in the twenty-first century. Endocrinol Metab Clin North Am. 2018 Jun; 47(2):427–440.
   PubMed Web of Science ®Google Scholar
• Geer EB, Shafiq I, Gordon MB, et al. Biochemical control during long-term follow-up of 230 adult patients with Cushing disease: a multicenter retrospective study. Endocr Pract. 2017 Aug;23(8)962–970.
   PubMed Web of Science ®Google Scholar
• Feelders RA, Newell-Price J, Pivonello R, et al. Advances in the medical treatment of Cushing's syndrome. Lancet Diabetes Endocrinol. 2019 Apr;7(4)300–312.
   PubMed Web of Science ®Google Scholar
• Ketoconazole tablets USP, 200 mg. Haifa Bay, Israel: Taro Pharmaceutical Industries Ltd.; 2017.
   Google Scholar
• European Medicines Agency. Ketoconazole HRA 200 mg tablets: summary of product characteristics. London. 2014.
   Google Scholar
• Newell-Price J. Ketoconazole as an adrenal steroidogenesis inhibitor: effectiveness and risks in the treatment of Cushing's disease. J Clin Endocrinol Metab. 2014 May; 99(5):1586–1588.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency Committee for Medicinal Products for Human Use. Ketoconazole HRA: assessment report. London. 2014.
   Google Scholar
• Boyce MJ, Baisley KJ, Warrington SJ, et al. Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study. Br J Clin Pharmacol. 2012 Mar;73(3)411–421.
   PubMed Web of Science ®Google Scholar
• Schwartz SL, Rendell M, Ahmann AJ, et al. Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase iIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus. Clin Ther. 2008 Jun;30(6)1081–1088.
   PubMed Web of Science ®Google Scholar
• Arakaki R, Welles B. Ketoconazole enantiomer for the treatment of diabetes mellitus. Expert Opin Investig Drugs. 2010 Feb; 19(2):185–194.
   PubMed Web of Science ®Google Scholar
• Rotstein DM, Kertesz DJ, Walker KA, et al. Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818–2825.
   PubMed Web of Science ®Google Scholar
• Auchus RJ, Wu Y, Liu J, et al. 2S,4R-ketoconazole is the relevant enantiomer of ketoconazole for cortisol synthesis inhibition: steroidogenic P450s inhibition involves multiple mechanisms [abstract]. Endocr Rev. 2018;39(2 suppl). https://www.endocrine.org/meetings-and-events/endo-annual-meetings?ID=46236 
   Google Scholar
• Thieroff-Ekerdt R, Lavin P, Abou-Gharbia M, et al. Pharmacology of COR-003 (levoketoconazole), an investigational treatment for endogenous Cushing's syndrome. 98th Annual Meeting and Expo of the Endocrine Society (ENDO); 2016 Apr 1–4; Boston, MA.
   Google Scholar
• Blass BE, Iyer P, Abou-Gharbia M, et al. Design, synthesis, and evaluation of (2S,4R)-ketoconazole sulfonamide analogs as potential treatments for metabolic syndrome. Bioorg Med Chem Lett. 2016 Dec 1;26(23)5825–5829.
   PubMed Web of Science ®Google Scholar
• Creemers SG, Feelders RA, de Jong FH, et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushing's syndrome treatment [published online ahead of print January 5, 2021]. J Clin Endocrinol Metab. 2021;106(4):e1618–e1630.
   PubMed Web of Science ®Google Scholar
• Pricen HM, Huijsmans CM, Kuipers F, et al. Ketoconazole blocks bile acid synthesis in hepatocyte monolayer cultures and in vivo in rat by inhibiting cholesterol 7a-hydroxylase. J Clin Invest. 1986;78(4):1064–1071.
   PubMed Web of Science ®Google Scholar
• Chiang JY. Bile acids: regulation of synthesis. J Lipid Res. 2009 Oct; 50(10):1955–1966.
   PubMed Web of Science ®Google Scholar
• Novotná A, Krasulová K, Bartoňková I, et al. Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 cells. PLoS One. 2014;9(10):e111286.
   PubMed Web of Science ®Google Scholar
• Dilmaghanian S, Gerber JG, Filler SG, et al. Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: testosterone and methadone as substrates. Chirality. 2004;16(2):79–85.
   PubMed Web of Science ®Google Scholar
• Stalla GK, Stalla J, Loeffler JP, et al. Pharmacological modulation of CRH-stimulated ACTH secretion by ketokonazole. Horm Metab Res Suppl. 1987;16:31–36.
   PubMedGoogle Scholar
• Herrera-Martinez AD, Feelders RA, De Herder WW, et al. Effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor cells. Horm Cancer. 2019 Jun;10(2-3)107–119.
   PubMed Web of Science ®Google Scholar
• Patalano R, Pivonello C, Solari D, et al. Ketoconazole induces inhibition of cell viability and apoptosis in an ACTH-secreting tumour cell line model [abstract EP 927]. Endocr Abst. 2017;49:3.
   Google Scholar
• Boudriau S, Demnati R, Swearingen D, et al. Differential effects of co-administration of racemic ketoconazole and levdexketoconazole of the pharmacokinetic profile of atorvastatin. American Society of Clinical Pharmacology and Therapeutics (ASCPT); 2008 Apr 2–5; Orlando, FL.
   Google Scholar
• Thieroff-Ekerdt RI, Mould DR Differential pharmacokinetics of levoketoconazole (COR-003), the single 2S,4R-enantiomer of ketoconazole, a new investigational drug for the treatment of Cushing's syndrome. 18th European Congress of Endocrinology (ECE); 2016 May 28–31; Munich, Germany.
   Google Scholar
• Gerber JG, Dilaghanian S, Gal J, et al. Stereoselective pharmacokinetics (PK) of oral ketoconazole (K) in healthy subjects. 43rd Interscience Conference on Antimicrobial Agents (ICAAC); 2003 Sept 14–17; Chicago, IL.
   Google Scholar
• Chin TW, Loeb M, Fong IW, et al. Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole. Antimicrob Agents Chemother. 1995 Aug;39(8)1671–1675.
   PubMed Web of Science ®Google Scholar
• Piscitelli SC, Goss TF, Wilton JH, et al. Effect of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother. 1991;35(9):1765–1771.
   PubMed Web of Science ®Google Scholar
• Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci. 2017 Sep; 106(9):2245–2250.
   PubMed Web of Science ®Google Scholar
• Fleseriu M, Pivonello R, Elenkova A, et al., Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol. 2019;7(211): 855–865.
   PubMedGoogle Scholar
• Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a try?. J Clin Endocrinol Metab. 2014 May;99(5):1623–1630.
   PubMed Web of Science ®Google Scholar
• Castinetti F, Morange I, Jaquet P, et al. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. Eur J Endocrinol. 2008 Jan;158(1)91–99.
   PubMed Web of Science ®Google Scholar
• Chung S, Son GH, Kim K, et al. Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta. 2011 May;1812(5)581–591.
   PubMed Web of Science ®Google Scholar
• Newell-Price J, Pivonello R, Tabarin A, et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease. Eur J Endocrinol. 2020 Feb;182(2)207–217.
   PubMed Web of Science ®Google Scholar
• Yoshida K, Fukuoka H, Odake Y, et al. Multiple salivary cortisol measurements are a useful tool to optimize metyrapone treatment in patients with Cushing's syndromes treatment: case presentations. Front Endocrinol (Lausanne). 2017;8:375.
   PubMed Web of Science ®Google Scholar
• Varlamov EV, Langlois F, Vila G, et al. Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing's syndrome: a practical approach. Eur J Endocrinol. 2021 Apr 22;184(5)R207–R224.
   PubMedGoogle Scholar
• Fleseriu M, Pivonello R, Elenkova A, et al. Levoketoconazole in the treatment of endogenous Cushing's syndrome: secondary endpoint results from a phase 3 study (SONICS). 16th International Pituitary Congress; 2019 Mar 20–22; New Orleans, LA.
   Google Scholar
• Varlamov EV, Han AJ, Fleseriu M, et al. Updates in adrenal steroidogenesis inhibitors for Cushing's syndrome - a practical guide. Best Pract Res Clin Endocrinol Metab. 2021 Feb 6;(1):101490. DOI: 10.1016/j.beem.2021.101490.
   PubMedGoogle Scholar
• Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating Cushing's syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015 Nov;100(11)4146–4154.
   PubMed Web of Science ®Google Scholar
• Geer EB, Salvatori R, Elenkova A, et al., Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome. Pituitary. 2021;24(1): 104–115.
   PubMed Web of Science ®Google Scholar
• Weber MM, Luppa P, Engelhardt D, et al. Inhibition of human adrenal androgen secretion by ketoconazole. Klin Wochenschr. 1989;67(14):707–712.
   PubMedGoogle Scholar
• Sonino N, Boscaro M, Paoletta A, et al. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. Clin Endocrinol (Oxf). 1991 Oct;35(4)347–352.
   PubMed Web of Science ®Google Scholar
• Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982;142(12):2137–2140.
   PubMed Web of Science ®Google Scholar
• Santen RJ, Van den Bossche H, Symoens J, et al. Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab. 1983;57(4):732–736.
   PubMed Web of Science ®Google Scholar
• DeFelice R, Johnson DG, Galgiani JN, et al. Gynecomastia with ketoconazole. Antimicrob Agents Chemother. 1981;19(6):1073–1074.
   PubMed Web of Science ®Google Scholar
• Mortimer RH, Cannell GR, Thew CM, et al. Ketoconazole and plasma and urine steroid levels in Cushing's disease. Clin Exp Pharmacol Physiol. 1991;18(8):563–569.
   PubMed Web of Science ®Google Scholar
• De Martin M, Toja PM, Goulene K, et al. No untoward effect of long-term ketoconazole administration on electrocardiographic QT interval in patients with Cushing's disease. Basic Clin Pharmacol Toxicol. 2016 Apr;118(4)279–283.
   PubMed Web of Science ®Google Scholar
• Pivonello R, De Martino MC, Iacuaniello D, et al. Metabolic alterations and cardiovascular outcomes of cortisol excess. Front Horm Res. 2016;46:54–65.
   PubMed Web of Science ®Google Scholar
• Mazziotti G, Formenti AM, Frara S, et al. Diabetes in Cushing disease. Curr Diab Rep. 2017 May;17(5)32.
   PubMed Web of Science ®Google Scholar
• Barbot M, Ceccato F, Scaroni C, et al. Diabetes mellitus secondary to Cushing's disease. Front Endocrinol (Lausanne). 2018;9:284.
   PubMed Web of Science ®Google Scholar
• Pivonello R, Elenkova A, Fleseriu M, et al. Levoketoconazole in the treatment of patients with Cushing's syndrome and diabetes mellitus: phase 3 SONICS results. Front Endocrinol. 2021;12:595894.
   PubMed Web of Science ®Google Scholar
• Young J, Bertherat J, Vantyghem MC, et al. Hepatic safety of ketoconazole in Cushing's syndrome: results of a compassionate use programme in France. Eur J Endocrinol. 2018 May;178(5):447–458.
   PubMed Web of Science ®Google Scholar
• Lewis JH, Zimmerman HJ, Benson GD, et al. Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology. 1984;86(3):503–513.
   PubMed Web of Science ®Google Scholar
• Lake-Bakaar G, Scheuer PJ, Sherlock S, et al. Hepatic reactions associated with ketoconazole in the United Kingdom. Br Med J (Clin Res Ed). 1987;294(11):419–422.
   PubMedGoogle Scholar
• Takemasa H, Nagatomo T, Abe H, et al. Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. Br J Pharmacol. 2008 Feb;153(3)439–447.
   PubMed Web of Science ®Google Scholar
• Moncet D, Morando DJ, Pitoia F, et al. Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome. Medicina (B Aires). 2007;67(1):26–31.
   PubMed Web of Science ®Google Scholar
• Verhelst JA, Trainer PJ, Howlett TA, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Clin Endocrinol (Oxf). 1991 Aug;35(2)169–178.
   PubMed Web of Science ®Google Scholar
• Baudry C, Coste J, Bou Khalil R, et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol. 2012 Oct;167(4)473–481.
   PubMed Web of Science ®Google Scholar
• Signifor (pasireotide) injection, for subcutaneous use. East Hanover, NJ: Novartis Pharmaceuticals. 2020.
   Google Scholar
• European Medicines Agency. Signifor (pasireotide) injection, for subcutaneous use: summary of product characteristics. Amsterdam. 2016.
   Google Scholar
• Isturisa (osilodrostat) tablets, for oral use. Lebanon, NJ: Recordati Rare Disease, Inc. 2020.
   Google Scholar
• European Medicines Agency. Isturisa (osilodrostat): summary of product characteristics. Amsterdam. 2020.
   Google Scholar
• Korlym (mifepristone) 300 mg tablets. Menlo Park, CA: Corcept Therapeutics Incorporated. 2019.
   Google Scholar
• Metopirone 250 mg: summary of product characateristics. London: HRA Pharma UK and Ireland Limited. 2017.
   Google Scholar
• Fleseriu M, Pivonello R, Young J, et al. Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing's disease. Pituitary. 2016 Apr;19(2)138–148.
   PubMed Web of Science ®Google Scholar
• Pivonello R, Fleseriu M, Newell-Price J, 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. Lancet Diabetes Endocrinol. 2020;8(9): 748–761.
   PubMed Web of Science ®Google Scholar
• Fleseriu M, Findling JW, Koch CA, et al. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014 Oct;99(10)3718–3727.
   PubMed Web of Science ®Google Scholar
• Boscaro M, Sonino N, Rampazzo A, et al. ACTH response to corticotropin releasing hormone in Cushing's disease before and after ketoconazole: in vivo and in vitro studies. Horm Metab Res Suppl. 1987;16:60–62.
   PubMedGoogle Scholar
• Correa-Silva SR, Nascif SO, Silva MR, et al. Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with Cushing's disease. Arq Bras Endocrinol Metab. 2007;51(7):1110–1117.
   PubMedGoogle Scholar
• Correa-Silva SR, Nascif SO, Molica P, et al. Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6). Clin Endocrinol (Oxf). 2010 Jan;72(1)70–75.
   PubMed Web of Science ®Google Scholar
• De Pedrini P, Tommaselli A, Montemurro G, et al. No effect of ketoconazole on thyroid function of normal subjects and hypothyroid patients. Int J Clin Pharmacol Res. 1988;8(6):485–488.
   PubMedGoogle Scholar
• Britton H, Shehab Z, Lightner E, et al. Adrenal response in children receiving high doses of ketoconazole for systemic coccidioidomycosis. J Pediatr. 1988 Mar;112(3)488–492.
   PubMed Web of Science ®Google Scholar
• Martikainen H, Heikkinen J, Ruokonen A, et al. Hormonal and clinical effects of ketoconazole in hirsute women. J Clin Endocrinol Metab. 1988;66(5):987–991.
   PubMed Web of Science ®Google Scholar
• Vidal-Puig AJ, Munoz-Torres M, Jodar-Gimeno E, et al. Ketoconazole therapy: hormonal and clinical effects in non-tumoral hyperandrogenism. Eur J Endocrinol. 1994;130(4):333–338.
   PubMed Web of Science ®Google Scholar
• Glass AR. Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve. J Clin Endocrinol Metab. 1986;63(5):1121–1125.
   PubMed Web of Science ®Google Scholar
• Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012 Mar 8;366(10)914–924.
   PubMed Web of Science ®Google Scholar
• Lacroix A, Gu F, Gallardo W, et al. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 2018;6(1):17–26.
   PubMed Web of Science ®Google Scholar
• Tritos NA. Adrenally directed medical therapies for Cushing syndrome. J Clin Endocrinol Metab. 2021 Jan 1; 106(1):16–25.
   PubMed Web of Science ®Google Scholar
• Feelders RA, De Bruin C, Pereira AM, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med. 2010 May 13;362(19)1846–1848.
   PubMed Web of Science ®Google Scholar
• Fleseriu M, Auchus RJ, Greenman Y, et al. Levoketoconazole in the treatment of endogenous Cushing's syndrome: extended evaluation phase results of the SONICS study. ECE 2020: 22nd European Congress of Endocrinology; Sept 5–9; virtual meeting. 2020.
   Google Scholar
• Zacharieva SZ, Pivonello R, Elenkova A, et al. Safety and efficacy of levoketoconazole in the treatment of endogenous Cushing's syndrome (LOGICS): a double-blind, placebo-controlled, withdrawal study. J Endocr Soc. 2020;4(Supplement_1):A572–A573.
   Google Scholar