Mitotane (Lysodren®) in the therapy of adrenocortical carcinoma

Mitotane, or o,p'-DDD (European tradename: Lysodren (R), HRA Pharma, Paris, France), is an orphan drug for the adjuvant therapy of adrenocortical carcinoma. As monotherapy, it is suggested ("suggested", not "recommended" - a lower level of recommendation) in tumours that have been macroscopically completely removed in healthy people, but that show a high risk of recurrence. Mitotane is directly membrane-toxic and inhibits many enzymes of adrenal steroid biosynthesis, induces CYP3A4 (by which many medications are metabolized) and 5 alpha-reductase (thereby reducing the conversion of testosterone to bioactive dihydrotestosterone) in a strong and sustained manner. The relative selectivity of the drug to the adrenals may be due to the inhibition by Mitotane of Sterol-O-Acyl-Transferase triggering lipid-mediated endoplasmatic reticulum stress and apoptosis of adrenocortical cells. Pharmacokinetically, the substance is distinguished by its long duration of action (up to 1-2 years after discontinuation). Effects and side effects are adrenal cell toxicity, the occurrence of primary adrenal insufficiency, acceleration of the breakdown of the necessary hydrocortisone treatment (which must therefore be given in doses at least twice as high as usual), a contraindication to pregnancy (disorders of sex differentiation caused by the reduction of 5 alpha-reductase activity), and - because receptivity is not affected - the necessity for a barrier method of contraception (due to acceleration of the metabolism of sex steroids). In the case of male hypergonadism, in symptomatic patients or in those with severe anaemia or osteoporosis, treatment with (or switching to) dihydrotestosterone could be considered. Thyroid function disorders with decreased TSH and FT4 are possible. In the case of alternatives, switching to drugs that are not substrates or are weaker substrates of CYP3A4 is recommended; otherwise, a dose titration, if necessary supported by therapeutic drug monitoring or surrogate laboratory parameters of the clinical effect. An up-to-date database can be found at .