O,p′-DDD (Mitotane) levels in plasma and tissues during chemotherapy and at autopsy

Slooten, H. van; Seters, A. P. van; D, Smeenk; Moolenaar, A. J.

doi:10.1007/bf00265384

Cited by 40 publications

(27 citation statements)

References 8 publications

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“…The model estimated the volume of distribution to be relatively high (161G68 l/kg LBM) and clearance to be relatively low (1.12G0.41 l/h). Moreover, previous observations of fatty tissue concentrations that were w200-fold higher than plasma concentrations are in accordance with this hypothesis (19). Since the time from baseline to peak variability in both groups seems to be comparable (3-5 h), the influence of food intake should be considered.…”

Section: European Journal Of Endocrinologysupporting

confidence: 80%

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Kerkhofs

Derijks

Ettaieb

et al. 2014

European Journal of Endocrinology

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Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (nZ7) and 17.0 mg/l (13.7-23.8) in the second group (nZ6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at tZ4 after morning dose and a change of 13% (range K14 to 33%) at tZ4 without morning dose (PZ0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

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Section: European Journal Of Endocrinologysupporting

confidence: 80%

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Kerkhofs

Derijks

Ettaieb

et al. 2014

European Journal of Endocrinology

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“…Although to our knowledge early studies did not report drug levels, two retrospective studies concluded that mitotane levels Ͼ 10 g/mL or 14 g/mL were associated with a higher response rate. 10,27,28 In the current study, no association was observed between mitotane levels Ͼ 10 g/mL or 14 g/mL and response, suggesting that mitotane levels did not have a significant effect on the efficacy of this treatment regimen.…”

Section: Discussioncontrasting

confidence: 54%

A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma

Abraham¹,

Bakke²,

Rutt³

et al. 2002

Cancer

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“…Our study highlights that monitoring of plasma mitotane concentrations is of particular interest in controlling hypercortisolism. The narrow therapeutic range of mitotane is well known, and a target plasma concentration between 14 and 20 mg/l is recommended in adrenocortical cancer (31,32,33). However, the target concentration for the anti-cortisolic effect is not well established.…”

Section: Discussionmentioning

confidence: 99%

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

Baudry

Coste

Khalil

et al. 2012

European Journal of Endocrinology

168

118

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Context: Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first-or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. Objective: Evaluation of the efficacy and tolerance of mitotane in CD patients. Design and setting: Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. Main outcome measure: Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). Results: Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5G8.9 mg/l, with a mean daily dose of 2.6G1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P!0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), PZ0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. Conclusion: Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

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O,p′-DDD (Mitotane) levels in plasma and tissues during chemotherapy and at autopsy

Cited by 40 publications

References 8 publications

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma

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

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