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 (>12 vs <12 months) or dose of medication per kilogram (>18 or <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-β-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.