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Expert Opinion on Drug Metabolism & Toxicology
How close are we to personalized mitotane dosing in the treatment of adrenocortical carcinoma? State of the art and future perspectives
Rebecca V. Steenaard, Madeleine H.T. Ettaieb, Thomas M.A. Kerkhofs & Harm R. Haak
To cite this article: Rebecca V. Steenaard, Madeleine H.T. Ettaieb, Thomas M.A. Kerkhofs & Harm R. Haak (2021): How close are we to personalized mitotane dosing in the treatment of adrenocortical carcinoma? State of the art and future perspectives, Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1080/17425255.2021.1921146
To link to this article: https://doi.org/10.1080/17425255.2021.1921146
Published online: 04 May 2021.
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How close are we to personalized mitotane dosing in the treatment of adrenocortical carcinoma? State of the art and future perspectives
Rebecca V. Steenaard (Da,b, Madeleine H.T. Ettaiebc, Thomas M.A. Kerkhofsd and Harm R. Haak (Da,b,e
ªDepartment of Internal Medicine, Máxima MC, Veldhoven, Eindhoven, The Netherlands; bMaastricht University, CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht, The Netherlands; “Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands; dDepartment of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre+, Maastricht, The Netherlands; eDepartment of Internal Medicine, Division of General Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands
ABSTRACT
Introduction: Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.
Areas covered: We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combina- tion therapy have not yet led to a potential dose adjustment for mitotane.
Expert opinion: Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.
ARTICLE HISTORY Received 8 March 2021 Accepted 20 April 2021
KEYWORDS Adrenocortical carcinoma; mitotane; personalized treatment; pharmacokinetics; pharmacogenetics
1. Introduction
Adrenocortical carcinoma (ACC) is a rare cancer with an inci- dence of 1 per million person-years [1]. Surgery is the main treatment modality. However, due to the often aggressive nature of ACC, risk of recurrence or metastasis is high and half of patients already have advanced disease upon presenta- tion. Mitotane is the only drug registered specifically for ACC. It is indicated as monotherapy or in combination with classical chemotherapy in patients with irresectable or metastatic dis- ease and increasingly used as adjuvant therapy after complete resection in patients at high risk for recurrent disease [2,3]. Many studies have been performed to find an alternative for mitotane, for example immunotherapy, but no therapy has successfully completed phase III clinical testing thus far [4].
Mitotane is derived from DDT, an insecticide with adreno- toxic properties [5]. Its first successful application in adreno- cortical carcinoma treatment dates back to 1959 [6]. It is a potent inhibitor of adrenal steroidogenesis. Its clinical ben- efit in adjuvant setting for patients with low risk of recurrence is currently under study in a randomized trial (ADIUVO clin- icaltrials.gov), and results are expected this year. Although not undisputed, current guidelines recommend adjuvant mitotane for two years in patients with high risk of recurrence based on several retrospective studies [2,3]. Studies on mitotane therapy for advanced disease are all observational with response to
mitotane monotherapy ranging from 10 to 30% and response to combination therapy ranging from 10 to 50% [2,3].
Treatment with mitotane comes with many clinical chal- lenges. Mitotane causes adrenal insufficiency requiring gluco- corticoid and incidentally mineralocorticoid supplementation. Dosages required for supplementation are often twice as high as in patients with Addison’s disease, due to mitotane induced steroid clearance and cortisol binding [2]. In addition, mito- tane causes many side-effects including gastro-intestinal, neu- rological and psychological effects, hypercholesterolemia and hepatotoxicity [2]. These side-effects often require the use of supportive drugs [7]. However, the choice of these supportive drugs is challenged by drug interactions, mostly due to CYP3A4 induction by mitotane [8,9].
Adequate mitotane dosing might be the most challenging aspect. A clinician must find the narrow balance between efficacy and toxicity. The optimal dose is different for each patient and can even differ over time in the same patient. With this review we aim to find the answer to the question how close we are to personalized dosing in adrenocortical carcinoma. To answer this, we have searched PubMed up till 1-1-2021 for references related to mitotane dosing, pharma- cokinetics of mitotane, pharmacogenetics of mitotane and combination therapy with mitotane in adrenocortical carci- noma (Table 1). We will conclude this review with an expert
Article highlights
· Mitotane dosing is difficult due to large differences in bioavailability, toxicity and effect.
· The optimal dosing regimen is currently based on expert opinion, not empirical evidence.
· Computerized pharmacokinetic models can predict plasma levels based on clinical characteristics such as distribution, clearance and lipid levels.
· The current models explain 40% of the plasma level variance, pharma- cogenetics are being investigated to find the unexplained variance.
. There are no supportive drugs yet that can lower the required mitotane dose while maintaining its adrenolytic effect.
This box summarizes key points contained in the article.
opinion from our research group and our view on future developments on this topic.
2. Personalized mitotane dosing
2.1. Dosing strategies
Traditionally, dosing of mitotane is based on expert opinion and guided by toxicity and plasma mitotane levels. The first assay for mitotane measurement was described in 1977 [10]. Mitotane plasma levels are currently measured by high per- formance liquid chromatography or gas liquid chromatogra- phy. Both measurements have a good agreement and the same cutoff values for therapeutic window [11]. Recently
a home-based measurement was proposed using dried capil- lary blood [12]. However, since there is no specific target range available yet for this assay, this method is currently not suita- ble for clinical practice.
The therapeutic window of mitotane was first established by Van Slooten, et al. in 1982 [13]. They proposed 14 mg/l as the cutoff for low or high plasma levels, based on the correla- tion with tumor response. Various studies confirmed this result and found that patients with plasma levels above 14 mg/l have improved progression-free survival [14-20]. The effect on overall survival was only evident in some of these studies. Most patients experienced side-effects, already starting at plasma levels of 5 mg/l. Patients with plasma levels above 20 mg/l have a significantly increased risk of experiencing severe side-effects, mostly neurological [13]. Therefore, the therapeutic window between 14 mg/l and 20 mg/l was pro- posed [2].
The challenge for physicians is to propose a dosing scheme to reach this therapeutic window while keeping side- effects tolerable for the patient. And even in patients with steady-state dosing, mitotane plasma levels have shown to be variable [21,22]. Physicians and their patients have to choose between a high-dose strategy which builds the dose up to 6 g/day in 1 week and a low-dose strategy which builds up to 4 g/day in 2 weeks. In both strategies the dose is adjusted based on the first plasma levels. A study comparing 20 patients on high-dose to 12 patients on low- dose mitotane showed no significant difference in reaching
| Study | Method | Pharmacokinetic parameters | Pharmacogenetic parameters |
|---|---|---|---|
| Kerkhofs | Iterative 2-stage Bayesian fit | Distribution volume: 161 L/kg | |
| 2015 [30] | 3-compartment model 20 patients, 302 plasma levels | Clearance: 0.94 L/h Covariates: lean body mass influences distribution | |
| Arshad | Non-linear mixed-effect | Distribution volume: 6086 L Clearance: 1 L/day+3.97 L/day/mg/L Covariates: mitotane increases enzyme synthesis which causes increased clearance | |
| 2018 [31] | 1-compartment model 76 patients, 1137 plasma levels | ||
| Cazaubon | Non-linear mixed-effect | Distribution volume: 8900 L Clearance: 70 L/day Covariates: triglyceride and high density lipoprotein decrease mitotane clearance | |
| 2019 [32] | 1-compartment model | ||
| 38 patients, 503 plasma levels | |||
| Yin | Non-linear mixed-effect | Distribution volume: 6210 L central compartment and 18,100 L peripheral compartment Clearance: 43 L/day Covariates: lean body weight and fat amount influence distribution | Reduced clearance rate: CYP2C19*2A (rs4244285) 44.9% SLCO1B1 571 T > C (rs4149057) 40.2% (heterozygote) and 30.2% (homozygote) SLCO1B3 699A>G (rs7311358) 39.9% |
| 2020 [33] | 2-compartment model 48 patients, 914 plasma levels, 1936 genetic variants | ||
| Mornar 2012 [36] | Case report with high mitotane plasma level RT-PCR of CYP2C9 and CYP2C19 | The patient was a CYP2C9 intermediate metabolizer and had a high plasma level of mitotane without its metabolites | |
| D'Avolio | 27 patients | CYP2B6*6 (rs3745274) correlated with high plasma level | |
| 2013 [37] | Genotype of CYP2B6 and ABCB1 in relation to mitotane plasma level after 3, 6, 9 and 12 months of therapy | ||
| Ronchi | 239 patients | CYP2W1 immunoreactivity associated with better | |
| 2014 [38] | qRT-PCR and immunohistochemistry of CYP2W1 | response to mitotane | |
| Altieri | 182 patients | CYP2W1*6 lower plasma levels and response | |
| 2020 [39] | CYP2W1 and CYP2B6 SNPs in germline DNA in relation to mitotane plasma levels | CYP2B6*6 higher plasma levels |
therapeutic window within 3 months or side effects between the two regimens [23]. However, there was a trend toward more patients reaching the desired plasma level within 3 months using a high start dose. A study on high-dose mitotane (>4 g/day, median 6 g/day in 2 weeks) showed 10 out of 22 patients reaching the therapeutic window within 3 months and an additional 4 patients after 3 months [24]. Three of these patients had severe side effects. These find- ings on the high-dose strategy were already demonstrated in a previous study that showed four patients out of six reached therapeutic levels within 4 weeks and toxic level within 6 weeks, on a rapidly progressive dose of 6-9 g/day in 2 weeks [25]. Three of these patients experienced reversible side effects, of which one severe (nausea grade 3). In con- trast, a series of eight patients on low-dose (2-3 g/day) mitotane treatment all reached the therapeutic window after 3-5 months, with acceptable toxicity in seven patients [26]. This suggests a more conservative approach to dosing can also lead to successful treatment with a more gradual increase in side-effects. Current guidelines recommend the high strategy dose for patients with good performance sta- tus as long as gastro-intestinal side-effects remain manage- able. For other patients, the low-dose strategy is recommended [2,3].
2.2. Pharmacokinetics
For many years it has been known that mitotane is a lipophilic drug with a low absorption rate and an extremely long half-life [27-29]. These characteristics illustrate why it takes weeks or months to reach steady-state concentrations. Several efforts have been made to construct pharmacokinetic models of mitotane. The aim of these studies is to improve clinical management of mitotane by helping the physician to predict the plasma level buildup in individual patients.
The first pharmacokinetic model was constructed using iterative 2-stage Bayesian fitting based on a population of 20 patients including 302 plasma level measurements [30]. This was a 3-compartment model with an estimated mitotane clearance of 0.94 L/h and volume of distribution of 161 L/kg. Later, several models were constructed by using non-linear mixed-effects modeling, another computerized technique that never before had been employed on this old drug.
Arshad, et al. composed a one-compartment model based on data of 76 patients including 1137 plasma level measure- ments [31]. This model includes a mechanism of enzyme auto- induction, which assumes that mitotane increases enzyme synthesis and by doing so causes increased clearance of mito- tane over time. Estimated clearance increase was 3.97 L/day per mg/L mitotane plasma level with fixed baseline clearance of 1 L/day. This model estimates the volume of distribution at 6086 L.
Cazaubon, et al. also constructed a one-compartment model, which was based on 38 patients and 503 plasma level measurements [32]. Clearance was estimated at 70 L/ day and volume of distribution at 8900 L. This model does not include a mechanism of enzyme induction, but does
identify a covariate effect of triglyceride (Tg) level and high- density lipoprotein (HDL) level, i.e. higher Tg and HDL levels result in decreased mitotane clearance.
Yin, et al. developed a two-compartment model based on data of 48 patients and 914 plasma level measurements [33]. A novel feature in this model is that it includes pharmacoge- netic variables which were added by genotyping 1936 genetic variants of enzymes and transporters involved in absorption, distribution metabolism and excretion of drugs. According to this model, single nucleotide polymorphisms in genes coding for the CYP2C19 enzyme and transporters SLCO1B3 and SLCO1B1 are associated with mitotane clearance. This model’s estimates of clearance was 43 L/day, volume of distribution was estimated at 6210 L for the central compartment and 18,100 L for the peripheral compartment.
2.3. Pharmacogenetics
The current pharmacokinetic models only explain 40% of the variance in mitotane plasma levels in individual patients. Genetic variation is expected to account for a considerable amount of the remaining variance. Even though the exact mechanism of mitotane metabolism is unknown, we do know that mitotane activation occurs by beta-, or alpha- hydroxylation into two active components, o,p-DDA and o, p-DDE [17,34]. Several variants of cytochrome p450 enzymes have been linked to this process and turned out to correlate with mitotane pharmacokinetics [35]. An individual with high mitotane plasma levels was found to be a CYP2C9 intermediate metabolizer [36]. The genotypic variant CYP2B6*6 (rs3745274), was found to correlate with mitotane higher plasma levels 3 and 6 months after start of treatment [37]. High CYP2W1 activity was associated with better response to mitotane therapy in terms of overall survival and progression-free survival, both in adjuvant and palliative setting [38].
A recent European multicenter study in 182 ACC patients confirmed the association of CYP2W1 and CYP2B6*6 with mitotane plasma levels [39]. Patients with a CYP2W1 wild- type had a better chance to reach therapeutic mitotane plasma levels, longer time to progression and higher disease control rate than patients with a CYP2W1*6 variation. Patients with CYP2B6*6 had a better chance to reach the therapeutic range, especially when a CYP2W1 wild-type was also present. However, these associations were only significant in patients with advanced ACC (N = 79), not in patients after radical resection who received mitotane as adjuvant treatment (N = 103). The authors suggest that local (i.e. tumoral) expres- sion of CYP2W1 and CYP2B6 could be responsible for this remarkable observation.
A recent publication by Yin, et al. was the first to propose a model including pharmacogenetic variables to aid mitotane dosing [33]. They identified three genetic variants to have a significant effect on mitotane clearance in 48 patients. Clearance was reduced by 44.9% in CYP2C19*2A carriers (rs4244285) and by 39.9% in SLCO1B3 699A>G carriers (rs7311358). Heterozygotic SLCO1B1 571 T > C carriers
(rs4149057) had 40.2% of the clearance levels of wild-type patients, and homozygotic carriers 30.2%. Together with lean body weight at the start of treatment and fat amount as a measure of mitotane distribution, this model explained almost 60% of total plasma level variance. Interestingly, the previous finding on CYP2B6, CYP2C9, and CYP2W1 were not replicated in this study.
The model was used to simulate individual reactions to different dosing regimens [33]. The optimal regimen in terms of time to reach therapeutic window, risk of toxicity and time within therapeutic window, was a fixed individual starting dose and adjustment after 100 days based on plasma levels. The fixed dose was dependent on the model parameters of the individual. This proposed model has not yet been vali- dated in an independent cohort.
2.4. Combination therapy
There have been several research efforts to increase mitotane bioavailability or function through co-medication. In theory, this might lead to a lower dose requirement of mitotane. Patients are already advised to take mitotane with a fatty product such as milk. This is found to increase mitotane absorption due to its lipophilic character [28]. Building on this lipophilic character, many different vehicles have been proposed and tested to increase bioavailability, such as nano- carriers, micellar formulation, micro-emulsions and liposomal mitotane [40-43]. These studies have thus far not let to a clinically usable solution.
For advanced ACC, mitotane can be combined with che- motherapy. The most frequently used combination is etopo- side, doxorubine, cisplatin and mitotane, based on the results of the FIRMACT trial [44]. In vivo studies have shown that mitotane works synergistically with doxorubicine and cisplatin, but surprisingly not with etoposide [45-47]. Many other che- motherapeutic and some immunotherapeutic drugs have also shown a synergistic effect with mitotane in vitro [48-54]. Even certain food and vitamin supplements have demonstrated an additive effect when administered with mitotane in ACC cell lines [55-57]. However, many of these findings have not been replicated and have not been tested in clinical studies or even ‘in vivo’. The compounds that have been studied in patients have not led to potential dose adjustment for mitotane [44,58]. Furthermore, caution is warranted in combination therapy since mitotane is known for its many drug interactions and antagonistic effects have been seen in vitro [59].
The role of lipids metabolism in mitotane function has been studied extensively. Mitotane induces increased LDL, HDL and Tg levels [60]. Importantly, the resulting high lipid levels in turn reduce mitotane efficacy by binding mitotane [61]. Thus, low- ering of lipid levels by use of statins, might increase the effect of mitotane. This hypothesis was confirmed in a retrospective study where patients on mitotane and rosuvastatin had better tumor control [62]. One of the cytotoxic effects of mitotane is caused by inducing endoplasmic reticulum (ER) stress by increasing intra- cellular free cholesterol levels [63,64]. ACC cell lines treated with rosuvastatin and mitotane showed increased intracellular free
cholesterol levels inducing apoptosis [65]. Apart from statins, new therapeutic compounds have been proposed to increase mitotane activity through increasing ER stress [66,67], by increas- ing intracellular free cholesterol levels [68] or by lowering mito- tane-lipid binding [69]. Not all tested compounds have resulted in a synergistic effect [70] and none of the findings have resulted in clinical trials or potential lowering of mitotane dosing.
3. Conclusion
Personalized dosing of mitotane is currently based on expert opinion guided by toxicity and plasma levels. Pharmacokinetic models based on clinical parameters with or without genetics variants are promising but not yet validated for clinical use. There are no supportive drugs yet that can lower the required mitotane dose while maintaining its adrenolytic effect.
4. Expert opinion
Mitotane is the only adjuvant treatment option for ACC and the cornerstone of palliative treatment. Finding the optimal dose is difficult due to large individual differences in bioavail- ability, toxicity and effect. Research groups are searching for alternatives, but thus far, no promising options exist. We therefore look to improve personalized dosing of mitotane.
Comparison of different dosing strategies have not resulted in a preferential regimen. The choice of starting dose is based on a subjective estimate of the patient’s performance status and personal customs of the physician. We are looking for a model that ideally would be based on individual patient characteristics beyond performance alone. Several computer- ized pharmacokinetic models have been proposed based on measurable characteristics predicting absorption, distribution, metabolism and elimination. Computerized tools like these are theoretically usable in clinical practice, but only by clinicians experienced with this kind of methods and only if the neces- sary software and data are available. None of these models are tested in real-world clinical practice against the current stan- dard, which is dosing based on clinician’s experience.
The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have shown a great promise to find this unexplained variance. We expect future research efforts can lead to the discovery of a genetic panel to assist mitotane dosing. However, discovery and vali- dation will take several more years. In addition, there are logistical and financial limitations to using genetic testing in clinical practice. We therefore do not see an added value for pharmacogenetics in personalized mitotane dosing at this moment.
For the near future, we do see possibilities in further devel- opment of the existing pharmacokinetic models using clinical characteristics. Self-learning computer models using clinical data, dosing data and plasma levels of large numbers of patients can be used to improve the current models. An example of a dataset suitable for this ‘machine learning’ is the Lysosafe Online® database. This database contains data on dosing and plasma levels of a large proportion of the
European ACC population. When combined with clinical data, a usable model can be produced.
Any model would need to be tested in a trial compared to the current ‘expert opinion dosing’. The control group should be a comparable center using either local customs or ideally one of the regimens used in the FIRM-ACT trial (low-dose or high-dose) [44]. The primary outcome should be time to reach adequate mitotane plasma level. The secondary outcomes should include time with plasma levels higher than the therapeutic window, experienced toxicity and progression-free survival time.
Before clinical implementation, any validated model has to fulfill two additional criteria. Firstly the model needs to be widely available and easy to use for clinicians. A web-based tool would meet that requirement. Secondly the model should be self-learning based on actual plasma levels and should provide both a starting dose advice as well as dose corrections during treatment. We believe that such a model could and should be available for clinical practice in the near future.
Funding
This paper was not funded.
Declaration of interest
The authors have received a research grant from HRA Pharma. The authors have no other relevant affiliations or financial involvement with any organi- zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
ORCID
Rebecca V. Steenaard @D http://orcid.org/0000-0002-8004-4331 Harm R. Haak [ http://orcid.org/0000-0001-7385-9359
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