Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma

Abstract

Context: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head.Objective: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. Patients/Interventions: Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low-or highdose regimen by the local investigator. Thirty-two patients could be evaluated in detail.Main Outcome Measure: The difference in median mitotane plasma levels between both treatment groups was measured. Conclusions: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

Foetal exposure to mitotane/Op'DDD: Post‐natal study of four children

“…For patients with ACC, pathological diagnosis and tumour stage were determined according to Weiss score and ENSAT staging system . Hormonal evaluation and assays were performed as previously described . In brief, cortisol, testosterone, Delta4Androstenedione, SDHEA, 17 OH progesterone and aldosterone were measured by RIA, ACTH by IRMA, active renin by ECIA or RIA performed in the accredited (COFRAC; http://www.cofrac.fr) clinical endocrinology laboratory in each centre.…”

“…Because of its cytolytic effects, adrenal insufficiency may persist after the elimination of the drug. Interference with gonadal function in both males and females is now established . Beside its effects on steroidogenic tissues, this molecule can also adversely affect central nervous system functions and can interfere with cholesterol and hepatic metabolism …”

Development of a Pharmacokinetic Model of Mitotane

“…12,22 In the first study, a high dose strategy was deployed in 22 patients, median cumulative dose administered within 3 months was 405 g (range, 157-546 g). 12,22 In the first study, a high dose strategy was deployed in 22 patients, median cumulative dose administered within 3 months was 405 g (range, 157-546 g).…”

“…12,22 In the first study, a high dose strategy was deployed in 22 patients, median cumulative dose administered within 3 months was 405 g (range, 157-546 g). 12 Median cumulative doses in both regimens were 495 g (range, 163-593 g, high dose) and 242 g (range, 97-541 g, low dose), respectively. In the second study, a low-dose strategy was prospectively compared with a high-dose strategy in 40 patients.…”

“…12 Despite a confounding effect of concomitant chemotherapy and the fact that a steady state was not reached during the study, a trend toward higher plasma levels using a higher initial dose was described. The inability to predict mitotane levels may lead to relative underdosing and a prolonged build-up phase in some patients, whereas others unexpectedly demonstrate high plasma levels early in therapy, causing increased toxicity.…”