Adrenal-targeted drugs
Drugs inhibiting adrenocortical steroidogenesis include ketoconazole, mitotane, etomidate and metyrapone. In general, use of these drugs requires careful clinical monitoring for adverse effects, including AI [77]. Ketoconazole has been widely used to treat CD because it inhibits several steps in adrenal steroid synthesis and reduces UFC in the majority of patients with CD [78]. However, it also inhibits androgen synthesis and is associated with liver toxicity in some patients [79]. There is little prospective information on the long-term use of adrenal-targeted agents [11, 80]; however, 1 small retrospective study showed promising results [81, 82]. Mitotane also inhibits several steps in steroidogenesis, and can be adrenolytic during long-term therapy at doses >4 g/day [77]. Because mitotane is sequestered in adipose tissue and eliminated slowly, pregnancy must be avoided for 5 years after discontinuation [77].
LCI699 is a novel inhibitor of 11β-hydroxylase (the final enzyme in the cortisol synthesis pathway) under development for several indications, including CD. In a recent proof-of-concept study in patients with CD (UFC >1.5× ULN), all participants (N = 12) achieved either UFC normalization or ≥50 % reduction from baseline after 70 days of treatment. While all patients experienced ≥1 AE, most were mild or moderate. Some AEs consistent with AI were reported, and resolved after dose reduction. Four patients experienced hypokalemia; all cases were managed without dose reduction, and 3 patients received oral potassium supplementation [83]. A larger-scale, 22-week expansion trial is currently underway [84]. A summary of potential therapeutic targets in CD is shown in Fig. 4 [85].
Fig. 4 Potential targets and medical therapies in Cushing’s disease. From Fleseriu, M (2012) Neurosurg Clin N Am volume 23, page 657 [85]. Reproduced with permission