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


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


METHODS
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.


METHODS
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.
MD, Department of Internal Medicine, Máxima Medical Center, Ds. Th. Fliednerstraat 1, 5631 BM Eindhoven, The Netherlands. t.kerkhofs@mmc.nl.
T M
TM
Kerkhofs
E
E
Baudin
M
M
Terzolo
B
B
Allolio
R
R
Chadarevian
H H
HH
Mueller
B
B
Skogseid
S
S
Leboulleux
F
F
Mantero
H R
HR
Haak
M
M
Fassnacht
D000302:Adrenal Cortex / Q000187:drug effects* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001711:Biotransformation; D003633:Dichlorodiphenyl Dichloroethylene / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009367:Neoplasm Staging; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D010648:Phenylacetates / Q000097:blood; D012720:Severity of Illness Index
D018931:Antineoplastic Agents, Hormonal; D010648:Phenylacetates; D003633:Dichlorodiphenyl Dichloroethylene; D008939:Mitotane