Introduction

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 apparent liver injury.

Background

Osilodrostat (oh sil” oh droe’ stat) is a small molecule inhibitor of cortisol synthesis used for patients with Cushing disease not eligible for or not cured by surgical resection. Osilodrostat lowers serum levels of cortisol and can decrease symptoms and signs of Cushing disease. In preregistration trials, osilodrostat reached the designated response rate in 86% of treated subjects. An important part of use of osilodrostat was the careful monitoring of cortisol and titration of the dose so as not to precipitate adrenal failure. Osilodrostat was approved in the United States in 2020 as therapy of patients with Cushing disease for whom surgery is not an option or has not been curative. Osilodrostat is available in tablets of 1, 5, and 10 mg under the brand name Isturisa. The recommended starting dosage is 2 mg twice daily, with subsequent careful titration of the dose in 1 to 2 mg increments at two-week intervals to achieve adequate suppression of serum cortisol levels. In registration trials that employed careful titration and monitoring, the most frequent adverse events were adrenal insufficiency (43%), fatigue (39%), nausea (37%), headache (31%), edema (21%), and lesser rates of arthralgia, rash, back pain, diarrhea, and dizziness. Uncommon but potentially serious adverse events included prolongation of the QTc interval, acute hypercortisolism, and adrenal failure. Monitoring of the electrocardiogram, blood pressure, serum cortisol and potassium levels, and signs of adrenal failure and hormonal changes (hirsutism, weight loss, worsening hypotension) is important. Osilodrostat should be prescribed only by health care personnel with knowledge and experience in managing hyper- and hypo-cortisolism.

Hepatotoxicity

In preregistration trials, mild, transient serum aminotransferase elevations occurred in 37 of 137 (27%) patients receiving osilodrostat for Cushing disease, but in only 8 (6%) patients were values above 3 times the upper limit of normal (ULN), and only 1 was above 5 times ULN (<1%). Furthermore, bilirubin levels remained normal and no patient developed symptomatic acute liver injury. In most instances, other causes for the liver test abnormalities were present including preexisting nonalcoholic fatty liver disease, gallstone disease, and hepatic metastases from the adrenal tumor. No patient required discontinuation of therapy for liver test abnormalities. Since its licensure and its more widescale clinical use, there have been no reports of acute liver injury attributed to osilodrostat.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The causes of liver test abnormalities during osilodrostat therapy of refractory Cushing disease are often unrelated to the drug and are attributable to comorbidities of patients with hypercortisolism, such as fatty liver disease, gallstone disease, or malignancy.

Outcome and Management

The product label for osilodrostat does not recommend monitoring of routine liver tests during therapy with osilodrostat, but testing patients before starting therapy is appropriate because of the frequency of comorbidities including liver disease in patients with hypercortisolism. Rise in serum aminotransferase levels during therapy should trigger evaluation for other possible causes. Persistence of unexplained ALT levels above 3 times the ULN or appearance of symptoms of liver injury or jaundice should lead to at least temporary discontinuation and more careful monitoring.

Drug Class: Endocrine Disease Agents