Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

in Endocrine-Related Cancer
Authors:
Linus Haberbosch Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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https://orcid.org/0000-0002-4464-0427
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Lukas Maurer Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Arvid Sandforth Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Partner of the German Center for Diabetes Research (DZD), Germany

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Charlotte Wernicke Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Joachim Spranger Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Charité Center for Cardiovascular Research, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

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Knut Mai Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Charité Center for Cardiovascular Research, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

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Reiner Jumpertz von Schwartzenberg Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Partner of the German Center for Diabetes Research (DZD), Germany

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Correspondence should be addressed to K Mai: knut.mai@charite.de
DOI:
https://doi.org/10.1530/ERC-21-0202
Volume/Issue:
Volume 29: Issue 3
Article Type:
Research Article
Page Range:
121–128
Online Publication Date:
03 Feb 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
8
Received Date:
17 Dec 2021
Accepted Date:
11 Jan 2022
Print Publication Date:
01 Mar 2022
Online Publication Date:
03 Feb 2022
Keywords:
mitotane; o,p’-DDD; adrenocortical carcinoma; spironolactone; hypokalemia

  • Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X & Bertherat J 2006 Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. Journal of Clinical Endocrinology and Metabolism 91 2650–2655. (https://doi.org/10.1210/jc.2005-2730)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Allolio B & Fassnacht M 2006 Clinical review: Adrenocortical carcinoma: clinical update. Journal of Clinical Endocrinology and Metabolism 91 2027–2037. (https://doi.org/10.1210/jc.2005-2639)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Altieri B, Sbiera S, Herterich S, De Francia S, Della Casa S, Calabrese A, Pontecorvi A, Quinkler M, Kienitz T & Mannelli M et al.2020 Effects of germline CYP2W1* 6 and CYP2B6* 6 single nucleotide polymorphisms on mitotane treatment in adrenocortical carcinoma: a multicenter ENSAT study. Cancers 12 359. (https://doi.org/10.3390/cancers12020359)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Arshad U, Taubert M, Kurlbaum M, Frechen S, Herterich S, Megerle F, Hamacher S, Fassnacht M, Fuhr U & Kroiss M 2018 Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients. European Journal of Endocrinology 179 287–297. (https://doi.org/10.1530/EJE-18-0342)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barzon L, Fallo F, Sonino N, Daniele O & Boscaro M 1997 Adrenocortical carcinoma: experience in 45 patients. Oncology 54 490–496. (https://doi.org/10.1159/000227608)

  • Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G & Schlumberger M 2001 Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p′DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 92 1385–1392. (https://doi.org/10.1002/1097-0142(20010915)92:6<1385::aid-cncr1461>3.0.co;2-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bergenstal DM, Hertz R, Lipsett MB & Moy RH 1960 Chemotherapy of adrenocortical cancer with o,p′ DDD. Annals of Internal Medicine 53 672–682. (https://doi.org/10.7326/0003-4819-53-4-672)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Winchester DJ, Kebebew E & Sturgeon C 2008 Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 113 3130–3136. (https://doi.org/10.1002/cncr.23886)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, Kirschner LS, Chae YK, Abdulkadir SA & Rademaker A et al.2019 Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. Journal of Clinical Endocrinology and Metabolism 104 6193–6200. (https://doi.org/10.1210/jc.2019-00600)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Castinetti F, Nieman LK, Reincke M & Newell-Price J 2021 Approach to the patient treated with steroidogenesis inhibitors. Journal of Clinical Endocrinology and Metabolism 106 2114–2123. (https://doi.org/10.1210/clinem/dgab122)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cazaubon Y, Talineau Y, Feliu C, Konecki C, Russello J, Mathieu O & Djerada Z 2019 Population pharmacokinetics modelling and simulation of mitotane in patients with adrenocortical carcinoma: an individualized dose regimen to target all patients at three months? Pharmaceutics 11 566. (https://doi.org/10.3390/pharmaceutics11110566)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Colby HD, O’Donnell JP, Flowers NL, Kossor DC, Johnson PB & Levitt M 1991 Relationship between covalent binding to microsomal protein and the destruction of adrenal cytochrome P-450 by spironolactone. Toxicology 67 143–154. (https://doi.org/10.1016/0300-483x(9190138-q)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Corso CR, Acco A, Bach C, Bonatto SJR, De Figueiredo BC & De Souza LM 2021 Pharmacological profile and effects of mitotane in adrenocortical carcinoma. British Journal of Clinical Pharmacology 87 2698–2710. (https://doi.org/10.1111/bcp.14721)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Daniel E & Newell-Price JD 2015 Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing’s syndrome. European Journal of Endocrinology 172 R263–R280. (https://doi.org/10.1530/EJE-14-1014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Decker CJ, Rashed MS, Baillie TA, Maltby D & Correia MA 1989 Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450. Biochemistry 28 5128–5136. (https://doi.org/10.1021/bi00438a033)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M, Mueller HH, Hahner S & Allolio B et al.2009 Limited prognostic value of the 2004 International Union against cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer 115 243–250. (https://doi.org/10.1002/cncr.24030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fassnacht M, Kroiss M & Allolio B 2013 Update in adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 98 4551–4564. (https://doi.org/10.1210/jc.2013-3020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, Kroiss M, Quinn DI, Hesseltine E & Ronchi CL et al.2015 Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet: Oncology 16 426–435. (https://doi.org/10.1016/S1470-2045(1570081-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, De Krijger R, Haak HR, Mihai R, Assie G & Terzolo M 2018 European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. European Journal of Endocrinology 179 G1–G46. (https://doi.org/10.1530/EJE-18-0608)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fries GF, Marrow Jr GS, Lester JW & Gordon CH 1971 Effect of microsomal enzyme inducing drugs on DDt and dieldrin elimination from cows. Journal of Dairy Science 54 364–368. (https://doi.org/10.3168/jds.s0022-0302(7185845-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fukumoto K, Kobayashi T, Tachibana K, Kato R, Tanaka K, Komamura K, Kamakura S, Kitakaze M & Ueno K 2006 Effect of amiodarone on the serum concentration/dose ratio of metoprolol in patients with cardiac arrhythmia. Drug Metabolism and Pharmacokinetics 21 501–505. (https://doi.org/10.2133/dmpk.21.501)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Haak HR, Hermans J, Van De Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ & Krans HM 1994 Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. British Journal of Cancer 69 947–951. (https://doi.org/10.1038/bjc.1994.183)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, Ahnert JR, Jimenez C, Lee JE & Perrier ND 2019 Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. Journal for ImmunoTherapy of Cancer 7 1. (https://doi.org/10.1186/s40425-019-0722-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hahner S & Fassnacht M 2005 Mitotane for adrenocortical carcinoma treatment. Current Opinion in Investigational Drugs 6 386–394.

  • Inouye M, Mio T & Sumino K 1987 Use of GC/MS/SIM for rapid determination of plasma levels of o,p′-DDD, o,p′-DDE and o,p′-DDA. Clinica Chimica Acta: International Journal of Clinical Chemistry 170 305–314. (https://doi.org/10.1016/0009-8981(8790141-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kerkhofs TM, Baudin E, Terzolo M, Allolio B, Chadarevian R, Mueller HH, Skogseid B, Leboulleux S, Mantero F & Haak HR et al.2013 Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 98 4759–4767. (https://doi.org/10.1210/jc.2013-2281)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kerkhofs TM, Derijks LJ, Ettaieb MH, Eekhoff EM, Neef C, Gelderblom H, Den Hartigh J, Guchelaar HJ & Haak HR 2014 Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring. European Journal of Endocrinology 171 677–683. (https://doi.org/10.1530/EJE-14-0388)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kerkhofs TM, Derijks LJ, Ettaieb H, Den Hartigh J, Neef K, Gelderblom H, Guchelaar HJ & Haak HR 2015 Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma. Therapeutic Drug Monitoring 37 58–65. (https://doi.org/10.1097/FTD.0000000000000102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kolkhof P & Barfacker L 2017 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development. Journal of Endocrinology 234 T125–T140. (https://doi.org/10.1530/JOE-16-0600)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Koschker AC, Fassnacht M, Hahner S, Weismann D & Allolio B 2006 Adrenocortical carcinoma – improving patient care by establishing new structures. Experimental and Clinical Endocrinology and Diabetes 114 45–51. (https://doi.org/10.1055/s-2006-923808)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kroiss M, Quinkler M, Lutz WK, Allolio B & Fassnacht M 2011 Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clinical Endocrinology 75 585–591. (https://doi.org/10.1111/j.1365-2265.2011.04214.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lacroix A 2010 Approach to the patient with adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 95 4812–4822. (https://doi.org/10.1210/jc.2010-0990)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, Wermke M, Hariharan S, Von Heydebreck A & Kasturi V et al.2018 Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. Journal for ImmunoTherapy of Cancer 6 111. (https://doi.org/10.1186/s40425-018-0424-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lund BO & Lund J 1995 Novel involvement of a mitochondrial steroid hydroxylase (P450c11) in xenobiotic metabolism. Journal of Biological Chemistry 270 20895–20897. (https://doi.org/10.1074/jbc.270.36.20895)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y & Blondeau P 1990 Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322 1195–1201. (https://doi.org/10.1056/NEJM199004263221705)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Menard R, Cutler G & Rifka S 1977 Spironolactone and adrenal cytochrome P-405: inhibition of Op'DDD (mitotane) induced adrenal atrophy and necrosis. In Read Before the 59th Annual Meeting of the Endocrine Society, Chica-Go.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nelson AA & Woodard G 1948 Adrenal cortical atrophy and liver damage produced in dogs by feeding 2,2-bis-(parachloro-phenyl)-1,1-dichloroethane. Federation Proceedings 7 277.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Puglisi S, Calabrese A, Basile V, Ceccato F, Scaroni C, Simeoli C, Torlontano M, Cannavo S, Arnaldi G & Stigliano A et al.2019 Mitotane concentrations influence the risk of recurrence in adrenocortical carcinoma patients on adjuvant treatment. Journal of Clinical Medicine 8 1850. (https://doi.org/10.3390/jcm8111850)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Puglisi S, Calabrese A, Basile V, Ceccato F, Scaroni C, Altieri B, Della Casa S, Loli P, Pivonello R & De Martino MC et al.2020 Mitotane concentrations influence outcome in patients with advanced adrenocortical carcinoma. Cancers 12 740. (https://doi.org/10.3390/cancers12030740)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quinkler M & Stewart PM 2010 Treatment of primary aldosteronism. Best Practice and Research: Clinical Endocrinology and Metabolism 24 923–932. (https://doi.org/10.1016/j.beem.2010.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, Capanu M, Zamarin D, Saltz LB & Ariyan CE et al.2020 PD-1 blockade in advanced adrenocortical carcinoma. Journal of Clinical Oncology 38 71–80. (https://doi.org/10.1200/JCO.19.01586)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rao SN & Habra MA 2016 5th International ACC Symposium: old syndromes with new biomarkers and new therapies with old medications. Hormones and Cancer 7 17–23. (https://doi.org/10.1007/s12672-015-0247-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rudberg I, Hendset M, Uthus LH, Molden E & Refsum H 2006 Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Therapeutic Drug Monitoring 28 102–105. (https://doi.org/10.1097/01.ftd.0000189899.23931.76)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Solymoss B, Classen HG & Varga S 1969 Increased hepatic microsomal activity induced by spironolactone and other steroids. Proceedings of the Society for Experimental Biology and Medicine 132 940–942. (https://doi.org/10.3181/00379727-132-34342)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Terzolo M, Pia A, Berruti A, Osella G, Alì A, Carbone V, Testa E, Dogliotti L & Angeli A 2000 Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. Journal of Clinical Endocrinology and Metabolism 85 2234–2238. (https://doi.org/10.1210/jcem.85.6.6619)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P & Grossrubatscher E et al.2007 Adjuvant mitotane treatment for adrenocortical carcinoma. New England Journal of Medicine 356 2372–2380. (https://doi.org/10.1056/NEJMoa063360)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Terzolo M, Baudin AE, Ardito A, Kroiss M, Leboulleux S, Daffara F, Perotti P, Feelders RA, Devries JH & Zaggia B et al.2013 Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. European Journal of Endocrinology 169 263–270. (https://doi.org/10.1530/EJE-13-0242)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Thölking G, Siats L, Fortmann C, Koch R, Hüsing A, Cicinnati VR, Gerth HU, Wolters HH, Anthoni C & Pavenstädt H et al.2016 Tacrolimus concentration/dose ratio is associated with renal function after liver transplantation. Annals of Transplantation 21 167–179. (https://doi.org/10.12659/aot.895898)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh Jd & Gelderblom H 2011 Mitotane has a strong and a durable inducing effect on CYP3A4 activity. European Journal of Endocrinology 164 621–626. (https://doi.org/10.1530/EJE-10-0956)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Veytsman I, Nieman L & Fojo T 2009 Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. Journal of Clinical Oncology 27 4619–4629. (https://doi.org/10.1200/JCO.2008.17.2775)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Waszut U, Szyszka P & Dworakowska D 2017 Understanding mitotane mode of action. Journal of Physiology and Pharmacology 68 13–26.

  • Westin AA, Reimers A, Helde G, Nakken KO & Brodtkorb E 2008 Serum concentration/dose ratio of levetiracetam before, during and after pregnancy. Seizure 17 192–198. (https://doi.org/10.1016/j.seizure.2007.11.027)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wortsman J & Soler NG 1977 Mitotane: spironolactone antagonism in Cushing’s syndrome. JAMA 238 2527–2527. (https://doi.org/10.1001/jama.238.23.2527)

  • Yin A, Ettaieb MHT, Swen JJ, Van Deun L, Kerkhofs TMA, Van Der Straaten RJHM, Corssmit EPM, Gelderblom H, Kerstens MN & Feelders RA et al.2021 Population pharmacokinetic and pharmacogenetic analysis of mitotane in patients with adrenocortical carcinoma: towards individualized dosing. Clinical Pharmacokinetics 60 89–102. (https://doi.org/10.1007/s40262-020-00913-y)

    • PubMed
    • Search Google Scholar
    • Export Citation