Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses

Abstract

Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6-8 g per day are often associated with severe adverse effects. This paper reports the results of much lower doses of o,p'-DDD (0.5-2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE. It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot. Steady state plasma levels of o,p'-DDD between 5-10 micrograms/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 micrograms/ml for several weeks may lead to relapses, whereas DDD-levels over 10 micrograms/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 micrograms/ml in plasma.

Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center

“…In our study, plasma mitotane concentrations R8.5 mg/l were associated with normal 24-h-UFC at all time-points during patient follow-up. The previously suggested therapeutic range of mitotane for control of Cushing's syndrome (34) appears to be lower than that for the antitumoral effect. This could improve tolerance, as a lower dose of mitotane would be needed to reach hormonal control in CD.…”

Irreversible Binding and Adrenocorticolytic Activity of the DDT Metabolite 3-Methylsulfonyl-DDE Examined in Tissue-Slice Culture

“…By virtue of its tissue-selective toxicity, o,p´-DDD is currently used as an adrenocorticolytic drug to treat adrenocortical carcinoma and Cushing's disease (5).…”

Mitotane and Carney Complex: ten years follow-up of a low-dose mitotane regimen inducing a sustained correction of hypercortisolism

“…8 Indeed, in our patient, by contrast to a pronounced reduction of plasma dehydroepiandrosterone sulfate (DEAS) and cortisol concentration, aldosterone levels were not affected by mitotane treatment. Donadille et al 13 described a successful treatment of hypercortisolism in 23 ectopic ACTH secretion syndrome patients with occult and/ or inoperable and/or metastatic tumors or severe hypercortisolism using long-term mitotane courses with a mean therapy duration of 1.8 ± 2.1 yr (range 0.06-9.7 y) and a mean daily dose of 3.3 ± 1.2 g. In our adult PPNAD patient, we used a well-tolerated low-dose mitotane regimen (0.750-1 g/day after initial dose of 4 g/day) and we obtained a long-term (10 years) complete and sustained regression of Cushing's features with a significant amelioration of quality of life.…”

“…[8][9][10][11] Furthermore, mitotane may be a suitable therapeutic option for CC subjects at increased surgical risk or refusing further surgical procedures. Here we report the long-term follow up, the time-course of mitotane and the steroid serum profile of a tenyear low-dose mitotane regimen inducing correction of severe hypercortisolism in a young woman with PPNAD and CC.…”