REVIEW ARTICLE
Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma
Matthias Kroiss*, Marcus Quinklert, Werner K. Lutz+, Bruno Allolio* and Martin Fassnacht*
*Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital Würzburg, and University of Würzburg, Würzburg, ¡Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
Summary
Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroeth- ane, (o,p’-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for vari- ous forms of glucocorticoid excess. Through still largely unknown mechanisms, mitotane inhibits adrenal steroid synthesis and adre- nocortical cell proliferation. Mitotane increases hepatic metabolism of cortisol, and an increased replacement dose of glucocorticoids is standard of care during mitotane treatment. Recently, sunitinib, a multityrosine kinase inhibitor (TKI), has been found to be rapidly metabolized by CYP3A4 during mitotane treatment, indicating clinically relevant drug interactions with mitotane. We here sum- marize the current evidence concerning mitotane-induced changes in hepatic monooxygenase expression, list drugs potentially affected by mitotane-related CYP3A4 induction and suggest alter- natives. For example, using standard doses of macrolide antibiotics is unlikely to reach sufficient plasma levels, making fluoroquinol- ones in many cases a superior choice. Similarly, statins such as sim- vastatin are metabolized by CYP3A4, whereas others like pravastatin are not. Importantly, in the past, several clinical trials using cytotoxic drugs but also targeted therapies in ACC yielded disappointing results. This lack of antineoplastic activity may be explained in part by insufficient drug exposure owing to enhanced drug metabolism induced by mitotane. Thus, induction of CYP3A4 by mitotane needs to be considered in the design of future clinical trials in ACC.
(Received 30 June 2011; returned for revision 21 July 2011; finally revised 18 August 2011; accepted 24 August 2011)
Introduction
The chlorinated hydrocarbon mitotane (1-(2-chlorophenyl)-1-(4- chlorophenyl)-2,2-dichloroethane, o,p’-DDD) is cytotoxic on the adrenal cortex and is used for the treatment for Cushing’s syn- drome and adrenocortical carcinoma (ACC). ACC is a rare tumour which is frequently diagnosed in late stages and shows a poor prog- nosis (see Ref. 1 for a recent review). The first publication demon- strating use of mitotane in humans with ACC is from 1959,2 but despite this long-standing use, its exact mechanism of action is still unknown. However, there is convincing evidence that mitotane inhibits adrenal steroid synthesis and adrenocortical cell prolifera- tion. Mitotane obtained FDA approval for the treatment for ACC in 1970 and EMA orphan drug status in 2002. Mitotane is now a cornerstone of ACC treatment both in an adjuvant setting3 and in metastatic disease.4
CYP3A4 induction by mitotane - current evidence
In a recent manuscript, van Erp and her colleagues from Leiden University Medical Center present an observation of four patients treated with mitotane for adrenocortical carcinoma (ACC), dem- onstrating an unexpectedly strong induction of CYP3A4 metabo- lism by mitotane.5 Van Erp and colleagues initially aimed at investigating the differences in the activity of cytochrome P450 monooxygenase 3A4 and its inhibitor grapefruit juice on the phar- macology of the multityrosine kinase inhibitor (TKI) sunitinib in a cohort of eight patients.6 They used orally administered midazolam as a phenotypic probe for CYP3A4. Surprisingly, they found an about 20-fold reduced exposure to midazolam (AUC0-12 h) but highly increased exposure to its metabolite 1-hydroxy midazolam in two ACC patients treated with mitotane. Accordingly, sunitinib levels were only about one-fifth of the expected values. To corrobo- rate the idea that mitotane leads to increased CYP3A4 activity in these patients, van Erp and colleagues performed additional phar- macokinetic analyses in two further patients and were able to con- firm increased metabolism of midazolam indicative of CYP3A4 upregulation.
The study has obvious limitations owing to the small number of subjects studied and its partly retrospective design. However, this work has the merit that a serendipitous finding in two patients has
Correspondence: Dr Matthias Kroiss, Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. Tel .: +49-931-201-39704; Fax: +49-931-201-61688; E-mail: Kroiss_M@klinik.uni-wuerzburg.de
been further investigated and now provides compelling evidence with important clinical implications.
CYP3A4 induction by mitotane - indirect evidence
In addition to the above-mentioned publication, there are further important pieces of evidence implicating induction of CYP3A4 by mitotane. First, the closely related insecticide 1,1,1-trichloro-2,2- bis-(4-chlorophenyl)ethane (DDT) has been demonstrated to induce liver microsomal enzymes7-9 and, more specifically, CYP3A4 through binding to the pregnane X receptor (PXR) in the HepG2 cell line and rat liver.10-12 Second, increased urinary 6-hydroxycor- tisol concentrations (7- to 10-fold) is a characteristic feature during mitotane treatment, hypothetically owing to CYP3A4 induc- tion.13,14 In fact, it has been appreciated early that an increase in peripheral metabolism of cortisol is apparent as early as on the first day of mitotane treatment and may persist for several months after withdrawal of mitotane.15,16 A decrease in adrenal steroid secretion can be observed only after treatment for longer time intervals. Simi- larly, treatment with phenytoin, a strong inducer of several P450 enzymes, also results in increased cortisol 6ß-hydroxylation, 17-19 and hence, this has been suggested as a marker of liver microsomal enzyme induction.20-22 In fact, for investigations on exposure to organochlorine compounds from the environment, the ratio 6- hydroxycortisol/cortisol has been exploited as a biomarker.23 Taken together, it is likely that increased requirement of glucocorticoids during mitotane treatment is to a large extent caused by CYP3A4- dependent cortisol 6-hydroxylation. However, induction of cortisol binding protein (CBG) by mitotane leading to reduced serum free cortisol contributes significantly to the increased glucocorticoid requirement during mitotane treatment.24,25
Although the inducing effect of mitotane on CYP3A4 has long been recognized, and increased hydrocortisone replacement doses are routinely prescribed during mitotane treatment,26 the far- reaching implications of CYP3A4 induction for concomitant drug administration have not yet been appreciated. It should be empha- sized in this context that the effect of mitotane may persist for months after discontinuation of the drug owing to its extremely long half-life.
Figure 1 illustrates a hypothetical model that summarizes these direct and indirect pieces of evidence implicating a significant induction of CYP3A4 metabolism by mitotane.
Potential drug interactions in patients treated with mitotane
CYP3A4 is one of the most important drug-metabolizing micro- somal monooxygenases (see Ref. 27,28 for reviews) and is mainly expressed in the liver and intestine. It is considered to be implicated in the metabolism of about 50% of the drugs on the market.29 In the absence of direct evidence for drug interactions with mitotane for almost all drugs, conclusions must be deduced from (i) pub- lished pharmacokinetic data on the metabolism of a given sub- stance by CYP3A4 and (ii) reports on diminished exposure to or reduced clinical efficacy of a respective drug when known inducers of CYP3A4 are co-administered. Known strong CYP3A4 inducers
Mitotane
RXR (?)
PXR (?)
CYP3A4-gene other P450 genes (?)
Substrate drugs (see Tables)
XREM
Inactive metabolites
CYP3A4-protein
are carbamazepine, phenytoin,30 dexamethasone,31 phenobarbi- tal,32 pioglitazone33 and rifampicin.34
Here, we review the published literature to guide physicians in the choice of drugs when co-administering mitotane. We will focus on drugs prone to interaction with mitotane and relevant to the clinical management of ACC patients for two aspects: (i) the treat- ment of complications of ACC (Table 1) and (ii) drugs with antitu- mour activity (Table 2). We also propose alternative drugs that we consider to be less susceptible to interaction with mitotane.
One common complication of glucocorticoid secreting ACC is hypertension. Dihydropyridine type calcium channel antagonists are frequently used and effective antihypertensive drugs. However, the exposure to felodipine and nisoldipine was found to be dimin- ished by approximately 90% when the potent CYP3A4 inducer phenytoin was co-administered.35,36 This appears to be a class effect because other dihydropyridines have similar pharmacoki- netic properties. Therefore, angiotensin converting enzyme (ACE) inhibitors, ß-adrenoreceptor antagonists, loop diuretics, thiazides, angiotensin 2 antagonists and a-adrenoreceptor antagonists should be considered as alternatives.
Antibiotics are another clinically relevant group of drugs prone to interactions. As an example, macrolide antibiotics such as clari- thromycin are frequently used in community-acquired pneumo- nia. Patients suffering from malignant tumours and in particular from tumour-induced Cushing’s syndrome are at risk of infections. Unfortunately, all macrolide antibiotics are subject to CYP3A4 metabolism.37 Hence, atypical pathogens should rather be targeted using fluoroquinolones such as ciprofloxacin or moxifloxacin.
One further example of drugs strongly metabolized by CYP3A4 are certain statins. Mitotane commonly entails hypercholesterola- emia which - in severe cases - may be treated with HMG-COA inhibitors.4 However, simvastatin and atorvastatin, two commonly used compounds of this class, are substrates of CYP3A4,38 whereas pravastatin39 and rosuvastatin (PI:Crestor; AstraZeneca Pharma- ceuticals LP, Wilmington, DE, USA) are not. Hence, pravastatin
| Indication | Substrates of CYP3A4* | Alternatives with lesser likelihood of drug interaction with mitotane |
|---|---|---|
| Insomnia | Benzodiazepines | Titration of the drug to a clinically desirable effect |
| Alprazolam7º | TDM during long-term use or if ineffective | |
| Diazepam | ||
| Midazolam71 | ||
| And others | ||
| Insomnia | Z-Drugs | Titration of the drug to a clinically desirable effect |
| (Benzodiazepine-related drugs) | ||
| Zopiclone (PI: Lunesta; Sunovion | ||
| Pharmaceuticals, Marlborough, MA, USA, 2011) Zolpidem (PI: Ambien, sanofi-aventis, Bridgewater, NJ, USA, 2010) | ||
| Contraception | Oral contraceptives | Mechanical contraception |
| Steroid hormones | Glucocorticoids | Titration to a clinically desirable effect in the setting |
| (see text for details) | Hydrocortisone | of hormone replacement |
| Prednisone | Titration according to surrogate laboratory parameters as | |
| Prednisolone | an antiphlogistic | |
| Dexamethasone | TDM in case of critical indication (intracranial pressure, e.g.) | |
| Testosterone | Dose adjustment following hormone measurement | |
| Oestradiol | ||
| Antiemetics | 5HT3-receptor antagonists | Metoclopramide |
| Ondansetron (PI: Zofran; GlaxoSmithKline, | Diphenhydramine | |
| Research Triangle Park, NC, USA, 2011) | ||
| Granisetron (PI: Kytril; Roche Laboratories, | ||
| Nutley, NJ, USA, 2010) | ||
| Analgesia | Certain opioids | Morphine |
| Fentanyl72 | Oxymorphine | |
| Methadone (PI: Oxycontin; Purdue Pharma LP, | Hydromorphone | |
| Stamford, CT, USA, 2010) | ||
| Oxycodone (PI: Methadone; Mallinckrodt, | ||
| Hazelwood, MO, USA, 2009) | ||
| Tramadol (PI:Tramadol ER; Par Pharmaceutical Inc., Woodcliff Lake, NJ, USA, 2011) | ||
| Hypertension | Dihydropyridines35,36 | ACE inhibitors |
| Amlodipine | a-adrenoreceptor antagonists | |
| Nifedipine | B-adrenoreceptor antagonists | |
| Nitrendipine | Angiotensin 2 antagonists | |
| And others | Loop diuretics | |
| Thiazide diuretics | ||
| Hypertension, class | Verapamil | ACE inhibitors |
| I antiarrhythmics | Diltiazem | B-adrenoreceptor antagonists |
| Antipsychotic | Haloperidol | Elevate the dose based on therapeutic drug monitoring |
| Hypercholesterolaemia | Certain HMG-CoA-reductase inhibitors39 | Pravastatin |
| Atorvastatin | Rosuvastatin | |
| Cerivastatin | ||
| Lovastatin | ||
| Simvastatin | ||
| Antibiotic (atypical pathogens) | Macrolide antibiotics | Azithromycin |
| Erythromycin37 | Moxifloxacin | |
| Clarithromycin73 | Ciprofloxacin |
PI, prescribing information. * See indicated reference for details on metabolism by CYP3A4.
(or rosuvastatin) should be the statin of choice in mitotane-treated patients.
The clinical dilemma is still more complicated because a number of drugs are inhibitors as well as substrates for CYP3A4, and this will result in an unpredictable effect of mitotane on the co-admin-
istered drug.40 This may (i) counteract the inducing effect of mito- tane and lead to less reduced plasma levels of this drug or (ii) outweigh the inducing effect of mitotane. Examples of CYP3A4 inhibitors are azole antimycotics41 (for a detailed review see Ref. 42). Ketoconazole is occasionally used to treat glucocorticoid
| Drug class* | Substrates of CYP3A4+ |
|---|---|
| Tyrosine kinase inhibitors | Axitinib |
| (see Ref. 68 for review) | Dasatinib |
| For vandetanib see | Erlotinib66 |
| (PI Caprelsa Astra Zeneca 2011) | Gefitinib65 |
| Imatinib67 | |
| Nilotinib | |
| Lapatinib | |
| Sorafenib# | |
| Sunitinib | |
| Vandetanib | |
| mTOR (mammalian target of apamycin) inhibitor | Everolimus |
| See PI: Afinitor, Novartis, 2010 | |
| Topoisomerase inhibitor | Etoposide |
| plus cisplatin and doxorubicin56,57 plus doxorubicin, vincristine62 | |
| Vinca alkaloids | Vincristinet |
| See PI: Vincristine Sulfate, Hospira Inc, Lake Forest, IL, 2007 | plus doxorubicin, etoposide62 |
| Taxols (see Ref. 74 for review) | Docetaxel |
| Anthracyclines | Doxorubicin |
| As a monotherapy (see Ref. 75) plus cyclophosphamide and cisplatin (see Ref. 76) plus etoposide and cisplatin56,57 plus etoposude and vincristine62 plus cisplatine and 5-FU (see Ref. 77) |
PI, prescribing information. * See indicated reference for details on metabo- lism by CYP3A4. tSee indicated reference for published clinical trials. #Drugs currently under investigation as a treatment for ACC.
excess in ACC but is a strong inhibitor of CYP3A4 and other important monooxygenases like CYP2C9.43,44 It has been proposed to administer ketoconazole as an inhibitor of CYP3A4 to reduce dosage of CYP3A4 substrates such as cyclosporine A.45-47 This has been demonstrated in a randomized clinical trial of heart trans- plantation recipients to be safe and cost-effective. 48
Mitotane is known to be metabolized in the adrenal cortex by B-hydroxylation and dechlorination to an acyl chloride derivative which reacts in an aqueous environment to the main metabolite o,p’-DDA (1,1-(o,p’-dichlorodiphenyl) acetic acid). o,p’-DDE (1,1- (o,p’-dichlorodiphenyl)-2,2 dichloroethene) is a minor metabolite resulting from a-hydroxylation (see Ref. 4,49 for review). The extent of extra-adrenal and - in particular - hepatic metabolism has not been investigated; metabolism by CYP3A4 is therefore one potential pathway which merits further research.
It is appealing to exploit CYP3A4 inhibition by ketoconazole in the context of mitotane-mediated CYP3A4 induction. However, the overall effect, also with respect to mitotane metabolic transfor- mation, is difficult to predict, and therapeutic drug monitoring is a prerequisite. In individual ACC patients, such an approach may be considered in specialized centres, preferably in the context of a clin- ical trial.
As antifungal agents, fluconazole, amphotericin B or griseofulvin may be better options according to the respective indication.
Further drugs for the treatment for Cushing’s syndrome are metyrapone, an 11-beta-hydroxylase inhibitor, and aminoglutethi- mide, an inhibitor of adrenal steroidogenesis (see Ref. 49 for review). Both aminoglutethimide (PI: Cytadren, Novartis, East Hanover, NJ, USA) and metyrapone50,51 are inducers of CYP3A4 with the latter also acting as an inhibitor.52 Drugs that are not substrates of CYP3A4 (but act as inhibitors or inducers) will not pose a problem when co-administered with mitotane.
It should be stressed that mitotane might and is likely to induce other monooxygenases, as demonstrated by the requirement of high warfarin doses during mitotane treatment to obtain thera- peutic anticoagulation.53 Warfarin is a known substrate of CYP2C9,54 and hence, it cannot be excluded that mitotane induces additional P450 monooxygenases. However, this awaits further investigation.
Hence in any individual case, the use of a particular drug should be initiated only after utmost consideration of potential interac- tions with the current medication. Helpful tools for this are com- mercial databases such as the LexiInteract (LexiCom Inc., http:// www.lexi.com) or Micromedex Drug Interactions (http://www. micromedex.com, Thomson Reuters) as well as open access resources on the internet such as the Flockhart list.55
In addition, drugs that are typically used for the treatment for ACC might be affected by CYP3A4 induction. Etoposide, doxoru- bicin and cisplatin in combination with mitotane are the most widely used chemotherapeutic regimens in metastatic ACC.56,57 Results of the first international randomized multicentre trial in ACC (FIRM-ACT) which compares this regimen to streptozotocin plus mitotane58 as first-line cytotoxic therapy are expected in the near future. Both doxorubicin and etoposide59,60 are substrates of CYP3A4, and hence, serum concentrations may be significantly reduced by cotreatment with mitotane potentially impacting on clinical activity. On the other hand, based on in vitro studies, mito- tane has been proposed to increase effects of cytotoxic drugs by inhibiting multidrug resistance P-glycoprotein (PgP), an activity that has so far not been demonstrated in vivo.61,62 The clinical rele- vance of drug interactions through PgP is uncertain at this moment. The effect of mitotane on PgP might therefore be clini- cally irrelevant. The question to which extent these potential inter- actions impact clinically on patient outcome requires detailed pharmacokinetic investigation. Hence, the mere potential of drug interactions should not entail the abandonment of a given regimen. Rather this fact should lead to increased awareness of drug interac- tions. Further cytotoxic drugs that undergo CYP3A4 metabolism are listed in Table 2. Of note, streptozotocin is not a CYP3A4 substrate. Likewise, the promising combination of gemcitabine with 5-fluorouracil or its orally bioavailable prodrug capecitabine63 is not subjected to metabolism by CYP3A4.
Importantly, insufficient pharmacologic exposure to study drugs may have seriously affected the results of clinical trials conducted in patients with metastatic ACC receiving mitotane therapy. In recent years, several small-molecule antineoplastic agents have been evaluated but yielded disappointing results.64 In 19 patients treated with gefitinib, an inhibitor of epidermal growth factor
receptor (EGFR) signalling, no response was observed.65 Likewise, only one minor response was observed in 10 patients treated with a combination of the EGFR kinase inhibitor erlotinib and the cyto- toxic drug gemcitabine.66 A small series of only four patients who were treated with imatinib, a tyrosine kinase inhibitor targeting c- kit and PDGF,67 found no response. Importantly, all three are sub- strates of CYP3A4,68,69 and hence, insufficient drug exposures may have been reached in all these clinical trials as most likely the majority of these patients were treated with mitotane in the past or even concomitantly.66
Actually, therapeutic drug monitoring (TDM) is the only way to address and further explore the potential effect of mitotane on co- administered drugs. Not only the effect of mitotane on substrates of CYP3A4 but also the effect of mitotane on substrates of other members of the cytochrome P450 enzyme family should be explored. Although at present TDM is routinely available only for few drugs, it seems to be essential in any clinical trials with patients currently or formerly treated with mitotane. It will become an indispensable tool in the near future with more widespread use of liquid chromatography tandem mass spectrometry (LC-MS/MS) instrumentation.
Conclusions
Taken together, it has been known for decades that mitotane induces hepatic cortisol metabolism, and as a clinical conse- quence, dose adjustments of glucocorticoid replacement therapy have been routinely implemented. However, the more general impact of mitotane on hepatic drug metabolism has been largely ignored, probably because many clinicians do not consider hydrocortisone replacement as drug treatment in the strict sense of the word. Importantly, the strong induction of CYP3A4 by mitotane most likely led to insufficient drug levels in some recent clinical studies potentially contributing to their disappointing results. Moreover, in daily practice, underdosing of several drugs (e.g. antibiotics) might have entailed serious negative conse- quences for ACC patients. In the future, circumspect design of clinical trials and educated choice of cotreatment should help to improve optimal outcome in adrenocortical carcinoma patients receiving mitotane.
Acknowledgements
We thank the members of the DFG Clinical Research Unit 124, the German Adrenal Network Improving Treatment and Medical EDucation (GANIMED) and the European Network for the Study of Adrenal Tumours (ENS@T) for helpful discussion. This publica- tion was supported by grants of the Deutsche Krebshilfe (grant # 107111 to M.F.), the Deutsche Forschungsgemeinschaft (grant # FA 466/3-1 to M.F.) and the German Ministry of Research BMBF (grant # 01KG0501 to B.A. and M.F.).
Disclosures
M.F. and B.A. are investigators of an HRA Pharma-supported trial on the pharmacokinetic of mitotane. M.F., M.Q. and B.A. are
investigators of a Pfizer-supported investigator-initiated trial of sunitinib, a substrate of CYP3A4, in ACC.
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