Sex Differences on Mitotane Concentration and Treatment Outcome in Patients with Adrenocortical Carcinoma

Allegra, Sarah; Puglisi, Soraya; Brescia, Irene Vita; Chiara, Francesco Di; Basile, Vittoria; Calabrese, Anna; Reimondo, Giuseppe; Francia, Silvia De

doi:10.3390/life11030266

Cited by 6 publications

(5 citation statements)

References 41 publications

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“… 39 In addition, a recent publication underlined that mitotane concentrations are strongly affected by gender as female patients treated with adjuvant mitotane showed significantly lower levels (7.6 mg/L versus 11.0 mg/L, p = 0.007) but were also more likely to experience toxic concentrations (8% versus 5%), which should be considered in the dosing process. 40 As current recommendations for adjuvant therapy are not fully satisfactory, assessment of potential biomarkers is of interest. The epithelial–mesenchymal transition related genes FSCN1 and FOXM1 were both strong independent negative prognostic factors if overexpressed in localized or advanced ACC and were suggested to be used as predictive tools.…”

Section: Adjuvant Therapy Of Accmentioning

confidence: 99%

Management of adrenocortical carcinoma: are we making progress?

et al. 2021

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Adrenocortical carcinoma (ACC) is a rare malignancy characterized by aggressive biology and potential endocrine activity. Surgery can offer cure for localized disease but more than half of patients relapse and primary unresectable or metastasized disease is frequent. Prognosis of metastatic ACC is still limited, with less than 15% of patients alive at 5 years. Recent advances in understanding the molecular profile of ACC underline the high complexity of this disease, which is characterized by limited drugable molecular targets as well as by a complex interplay between a yet scarcely understood microenvironment and potential endocrine activity. Particularly steroid-excess further complicates therapeutic concepts such as immunotherapy, which have markedly improved outcome in other disease entities. To date, mitotane remains the only approved drug for adjuvant and palliative care in ACC. Standard chemotherapy-based protocols with cisplatin, doxorubicin and etoposide offer only marginal improvement in long-term outcome and the number of clinical trials conducted is low due to the rarity of the disease. In the current review, we summarize principles of oncological management for ACC from localized to advanced disease and discuss novel therapeutic strategies, including targeted therapies such as tyrosine kinase inhibitors and antibodies, immunotherapy with a focus on checkpoint inhibitors, individualized treatment concepts based on molecular characterization by next generation sequencing methods, the role of theranostics and evolvement of adjuvant therapy.

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Section: Adjuvant Therapy Of Accmentioning

confidence: 99%

Management of adrenocortical carcinoma: are we making progress?

et al. 2021

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“…In both cases, the o,p′-DDD and o,p′-DDE levels were lower in females (F) than males (M) (o,p′-DDD; F/M; 7.6/11.0 µg/ml and o,p′-DDE; F/M; 0.37/0.82 µg/ml). Accordingly, it was also observed that fewer female patients reached and maintained the mitotane level in therapeutic range [ 64 ].…”

Section: Mitotanementioning

confidence: 99%

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging

Haider

Ahmad

Groll

et al. 2021

Eur J Drug Metab Pharmacokinet

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Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren ® ). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably.

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“…Nevertheless, no association of weight or BMI with the blood mitotane concentration was found in the present real-world study. Although two studies found that sex can significantly influence the achievement of the therapeutic concentration of mitotane ( 19 , 35 ), the results of both are controversial. One found that fewer female patients than males were able to achieve and maintain the therapeutic range of 14–20 μg/ml, suggesting that females may be a risk factor for mitotane treatment failure, which presumably stems from effects of sex hormones on drug absorption ( 19 ), whereas another study showed that male patients required higher doses of mitotane than female patients to reach the mitotane therapeutic window ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas other studies have shown that the level of mitotane has a poor correlation with administration dosage indicates that there are other factors that may affect the target concentrations of mitotane ( 17 , 18 ). In addition, sex differences in mitotane concentration are still controversial ( 15 , 19 ), and the unexplained pharmacokinetic variability of mitotane remains high.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Cumulative Dose and Polymorphisms in CYP2B6 on the Mitotane Plasma Trough Concentrations in Chinese Patients With Advanced Adrenocortical Carcinoma

Liu

Shang

et al. 2022

Front. Oncol.

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Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00–22.50) with a median dose of 2 g/day (2.00–2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.

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Sex Differences on Mitotane Concentration and Treatment Outcome in Patients with Adrenocortical Carcinoma

Cited by 6 publications

References 41 publications

Management of adrenocortical carcinoma: are we making progress?

Management of adrenocortical carcinoma: are we making progress?

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging

The Effects of Cumulative Dose and Polymorphisms in CYP2B6 on the Mitotane Plasma Trough Concentrations in Chinese Patients With Advanced Adrenocortical Carcinoma

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