Levoketoconazole

Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections. CS is most commonly caused by an ACTH-producing pituitary adenoma (ACTH-dependent CS) but may also be caused by an adrenal adenoma, adrenal carcinoma, or adrenal hyperplasia (ACTH-independent CS). As hypercortisolism is associated with significant morbidity and increased mortality, the primary goal of therapy is to normalize cortisol levels, either through surgical resection of the associated tumour or, when surgery is unsuccessful or inappropriate, radiological or chemotherapeutic treatment.

Different medications target different axes of the underlying etiology of CS; steroidogenic enzyme inhibitors are effective against all forms of CS. Ketoconazole, which is indicated for endogenous CS by the EMA and used for the same indication off-label in the US, is a racemate of 2S,4R (levoketoconazole) and 2R,4S (dextroketoconazole) cis-enantiomers known to inhibit multiple CYP450 enzymes. Studies using enantiomerically pure versions deduced that levoketoconazole is between 1.2-2.7 times more potent at inhibiting the key steroidogenic enzymes CYP11A1, CYP11B1, CYP11B2, and CYP17A1 than racemic ketoconazole, and ~15-25 times more potent than dextroketoconazole, suggesting that the majority of the therapeutic efficacy of ketoconazole in CS is due to levoketoconazole. Hence, levoketoconazole directly inhibits key enzymes in cortisol and testosterone synthesis.

As levoketoconazole is a more potent steroidogenic inhibitor than ketoconazole, lower concentrations should achieve the same therapeutic effect and may also decrease the risk of hepatic toxicity. In addition to the dose consideration, levoketoconazole is 12 times less potent than dextroketoconazole at inhibiting CYP7A1, a rate-limiting enzyme for bile acid synthesis. However, levoketoconazole is roughly two times more potent at inhibiting CYP3A4 than dextroketoconazole.