Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report
Nadia Jebabli, Emna Gaïes, Hanen Eljebari, Rim Charfi, Mohamed Lakhal, Anis Klouz, Issam Salouage and Sameh Trabelsi
Service de Pharmacologie Clinique, Centre National de Pharmacovigilance de Tunis, Tunisie
Text received November 6th, 2014; accepted June 2nd, 2015 This case report was notified to National Center of Pharmacovigilance of Tunis (Tunisia) on November 14th, 2012
Abstract - Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer.
Keywords: mitotane; mitotane intoxication; plasmatic level
Résumé - Contribution à la surveillance thérapeutique dans l’évalua- tion des effets indésirables toxiques du mitotane : à propos d’un cas. Le mitotane a des effets secondaires graves ; son utilisation à des doses faibles semble être tolérée. Le dosage de la concentration plasmatique du mitotane est recommandé. Nous rapportons le cas d’un homme âgé de 47 ans ayant un cancer corticosurrenalien ayant des concentrations plasmatiques toxique avec des doses faible de mitotane.
Mots clés : mitotane ; intoxication au mitotane ; concentrations plasma- tiques
Abbreviations: see end of article.
1. Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive solid tumor characterized by a 5-year survival rate of below 15% for met- astatic disease.[1-4] Mitotane therapy continues to be a cornerstone of ACC treatment, as outlined by a recent consensus on adjuvant ACC therapy.[5] The objective response rate for mitotane has been
Mitotane concentration depending on the dose administration
45
Plasmatic level of mitotane (mg/L)
40
Cessation of mitotane
35
30
25
Readministration of mitotane
20
15
10
5
0
3
3,5
3,5
3,5
2
2
2
Dose of mitotane (g)
reported in prospective or retrospective studies as between 10 and 33%, and it has been suggested that mitotane has a prognostic impact for patients with metastatic ACC.[6-8]
Mitotane, is a compound derived from the insecticide dichloro- diphenyl-dichloroethane, having a potent adrenotoxic effects and is able to block cortisol synthesis. It is widely used in the treatment of ACC. At low dose regimen (1-3 g) mitotane seemed to be tolerated and at doses varying between 6 and 10 g it provided serious side effects.[1,2]
We report herein a case of toxic plasma levels in a patient treated with low dose regimen of mitotane.
2. Case report
On November 2011, a 47 years old man was treated with mito- tane for ACC administered orally at a starting dose of 3 g daily and progressively increased to 3.5 g on the 16th of February 2012 to reach the therapeutic range (defined as mitotane plasma levels between 14-20 mg/L).[3] One year after the initiation of mitotane the patient presented asthenia, nausea, vomiting and abdominal bloat- ing. A toxicity of mitotane was suspected and so therapeutic moni- toring of this drug was been required. Plasmatic levels measured by high performance liquid chromatography (HPLC) showed a con- centration about 42 mg/L. Mitotane was stopped, and after 1 and 2 months, concentrations decreased respectively to 29 and 20 mg/ L. Evolution was spontaneously and progressively favourable. Mito- tane was readministrated at dose of 2 g daily, at this dose the con- centration of mitotane was 11.4 and increased to 17.4 mg/L then to 19.96 (figure 1). These concentrations were in therapeutic range and showed no recurrence of asthenia, nausea and vomiting.
3. Discussion
Mitotane has been employed in the treatment of ACC over the last 50 years and it is generally regarded as a toxic drug with a narrow ther- apeutic index. Its pharmacological properties and exact mechanism
of action are still debated. It has been suggested that its therapeutic effect is dose-dependent.[4] A significant increase in neurological tox- icity has been reported when plasma mitotane levels exceed 20 mg/L. Therefore, mitotane plasma monitoring is currently recommended for targeting and maintaining plasma levels between 14 and 20 mg/L.[5]
In fact, it was reported that the toxicity of mitotane represents a major limit to its suitability in the treatment of ACC patients. Mito- tane plasma levels > 30 µg/mL is a rare event and suggest that the plasma mitotane should not be exceeded this value until a better understanding of the mechanism that drive clinical toxicity. [7]
In our case a toxic mitotane concentration (42 mg/L) with low dose regimen was observed. The monitoring of mitotane levels helped us to make individual dose adjustments, thus reducing toxic effects. Moreover, it was reported previously the possibility to design a standard schedule for mitotane treatment consisting of 3 g daily for about 3-4 months (or, if not tolerated, 2 g for 5-6 months) and then apering to 1-2 g to be taken chronically. Mitotane dose reduction after reaching the threshold is critical to avoid toxicity. [7] This protocol is generally well tolerated, and is able to provide ther- apeutic concentrations of the drug. In another hand, Desnost et al. found that high dose strategy defined as median dose of 6 g/day of mitotane over 6 weeks allowed 27% of ACC patients to reach the 14 mg/L therapeutic plasma mitotane level within 1 month and 45% of patients within 3 months. They suggest that mitotane dose should be readjusted according to plasma mitotane levels at 1 or/and 2 months and according patient tolerances. [8] Otherwise, Kasperlik reported that both high and low doses of mitotane are necessary. [7] Kerkhofs et al. conclude after a comparison of two mitotane starting dose regimen that for mitotane monotherapy the high-dose approach is favourable. Whereas, for combination therapy a lower dose seems reasonable.[9] It seems that the best method is to measure plasma mitotane concentration to choose the optimal mitotane dose.[10] In fact it is the only confirmed predictor of tumor response to mitotane therapy.[8] Preclinical studies have suggested that 1,1-(o,p’-dichlo- rodiphenyl) acetic acid (o,p’DDA) is the active metabolite of mito- tane. However, a recent study conducted by Hescot et al. confirm that o,p’DDA is very unlikely an effective metabolite of mitotane to control adrenocortical cell proliferation.[11] In our study, we focused only on mitotane concentration. We didn’t quantified o,p’DDA in our study.
Terzolo et al. confirm that there is currently controversy on the best dosing regimen to initiate mitotane therapy. In fact a high-dose regimen has been advocated to allow a rapid rise of plasma mitotane concentrations in order to avoid any delay in drug activity; however, toxicity associated with such a regimen is of concern. On the other hand, also a low dose regimen, potentially better tolerated, is able to provide target mitotane concentrations, but with a time lag of sev- eral months from treatment start. [5]
In our case, one year after mitotane low-dose regimen initiation, plasma levels of mitotane reached a toxic level. A dose adjustment according to plasma mitotane levels was the best choice for achiev- ing mitotane plasma levels of 14 mg/L.
The increase in plasma concentrations is in general slow and highly variable. Potential explanations are related to effects on enzyme induction by concomitant drugs and differences in intestinal absorption, which may also be affected by ingested food. Also, recent data show that individual genetic differences are significantly associated with mitotane levels. In abscence of baseline predictors early measurements constitute the only signal whether a given patient has a high probability of reaching the therapeutic level in time.[ [9]
In conclusion, therapeutic drug monitoring of mitotane is useful even with low doses in order to avoid drug toxicity which can be observed in some cases.
Conflicts of interests. None to declare.
Abbreviations. ACC: adrenocortical carninoma; HPLC: high performance liquid chromatography.
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Correspondence and offprints: Nadia Jebabli, Service de Pharmacologie Clinique, Centre National de Pharmacovigilance, 9 avenue Dr. Zouheir Essafi, 1006 Tunis, Tunisie.
E-mail: nadiajebabli@yahoo.fr