Adrenal response in children receiving high doses of ketoconazole for systemic coccidioidomycosis

The effect of ketoconazole on adrenal cortical function was studied in 10 prepubertal children receiving long-term (3 to 52 months) high-dose (10 to 23 mg/kg/d) orally administered ketoconazole treatment because of systemic coccidioidomycosis. Four hours after the once daily morning dose of ketoconazole, the patients had significantly elevated baseline desoxycorticosterone (DOC) and precursor/product ratios, and blunted cortisol and aldosterone responses to ACTH stimulation. Twenty-four hours after ketoconazole ingestion, both DOC and DOC/corticosterone ratio were approaching normal; the cortisol response to ACTH was normal in all but two of the 10 study patients, and these two had significantly improved response compared with their own 4-hour values. There appeared to be no differential adrenal response related to either duration of treatment (greater than 12 vs less than 12 months) or dose of medication per kilogram (greater than 18 or less than 18 mg/kg/d). Our data suggest that ketoconazole impairs production of cortisol and aldosterone by imposing a partial and temporary block at the 11-beta-hydroxylase step of steroid hormone synthesis. None of the patients required adrenal steroid replacement therapy in times of acute illness or surgery, and none had clinical evidence of adrenal insufficiency.