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J Clin Endocrinol Metab. 2013 Dec;98(12):4759-67. doi: 10.1210/jc.2013-2281. Epub 2013 Sep 20.

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

Author information

1
MD, Department of Internal Medicine, Máxima Medical Center, Ds. Th. Fliednerstraat 1, 5631 BM Eindhoven, The Netherlands. t.kerkhofs@mmc.nl.

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.

DESIGN/SETTING:

This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks.

PATIENTS/INTERVENTIONS:

Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose 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.

RESULTS:

Despite a difference in mean cumulative dose (440 ± 142 g vs 272 ± 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 ± 494 mg/L · d vs 555 ± 168 mg/L · d (P = .080).

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.

PMID:
24057287
DOI:
10.1210/jc.2013-2281
[Indexed for MEDLINE]
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