Advantages of everolimus therapeutic drug monitoring in oncology when drug–drug interaction is suspected: A case report

Abstract

Introduction

Drug interactions involving everolimus are fairly well known because of its common use, primarily as an immunosuppressant. Several recommendations regarding therapeutic drug monitoring are also available for the use of everolimus-based immunosuppression regimens. However, everolimus use in oncology differs substantially, particularly because of the high doses involved. Therapeutic drug monitoring, although sometimes necessary, is not recommended as a routine in oncology. Thus, it was deemed inapplicable due to the lack of clear recommendations.

Case report

Here, we present a case where a patient was prescribed everolimus for renal cell carcinoma. The patient benefitted from a pharmaceutical consultation prior to treatment initiation, and a drug interaction with verapamil was suspected.

Management and outcome: Therapeutic drug monitoring of everolimus was proposed. Based on the everolimus values reported in the literature, trough plasma concentration in the patient was greatly increased. The patient was then diagnosed with grade 4 oral mucositis, thereby requiring temporary suspension of everolimus treatment. Management of adverse effects was performed through multiple medicated mouthwashes.

Discussion

Therapeutic drug monitoring for everolimus is important for potential drug interactions or the occurrence of severe adverse events. In such cases, dose adjustments should be managed according to everolimus plasma concentrations. Clear oncological recommendations regarding plasma everolimus thresholds are required for a successful follow-up of the patient’s condition and to ensure adequate response to treatment.

Keywords

Therapeutic drug monitoring everolimus drug–drug interaction verapamil renal cell carcinoma

Introduction

Evaluation of the risk of drug interactions prior to the implementation of oral chemotherapy treatment has become a priority for clinical pharmacists,¹ especially when the risk increases relative to the frequency of oral intake. The effectiveness of a treatment is directly dependent on many pharmacokinetic parameters, besides the intravenous route of administration.² For instance, drug absorption can vary with diet and co-administration of medicines, and hepatic first-pass metabolism can be influenced by enzymatic inducers and inhibitors.

Everolimus is a key serine-threonine kinase marketed under the product name CERTICAN®, and it functions as an immunosuppressant, selectively inhibiting mammalian target of rapamycin (mTOR). In this case, everolimus was used as an anti-cancer agent under the name AFINITOR® or VOTUBIA®. Everolimus reduces the levels of vascular endothelial growth factor (VEGF), inhibiting tumor angiogenic processes. Additionally, everolimus is a potent inhibitor of the growth and proliferation of tumors, endothelial cells, fibroblasts, and blood-vessel-associated smooth muscle cells. By reducing in vivo glycolysis in solid tumors, everolimus can counteract the upregulation of mTOR activity in many human cancers. Everolimus is also indicated for the treatment of patients with advanced renal cell carcinoma (RCC), whose disease has progressed during or after treatment with VEGF-targeted therapy.³

Case report

We present here the case of a 62-year-old woman with a renal mass that was first discovered in 2007 (Figure 1). At that time, the patient refused surgery. In 2017, she experienced deterioration in her general condition, which also affected her psychological well-being and her ability to accept her current situation given a past trauma. The patient was often tired and physically restricted in her daily tasks with an Eastern Cooperative Oncology Group performance status of 2. During examination, a left renal mass of approximately 10 cm was discovered with thrombosis of the left renal vein. The patient presented hepatic and regional lymph node metastases at this stage. The biopsy then confirmed the diagnosis of RCC stage IV (T_3cN₁M₁). Because of her history of left renal vein thrombosis, which contraindicated the use of a VEGF-targeted anti-angiogenic tyrosine kinase inhibitor, such as sunitinib, treatment with everolimus was discussed and recommended in a multidisciplinary consultation meeting.

The patient had many comorbidities, namely asthma, urticaria, Bouveret-Hoffmann syndrome (paroxysmal tachycardia), diabetes, and hypothyroidism. She also had moderate hepatic impairment with total bilirubin levels greater than 1.6 times the upper normal limit. Her condition was, thus, stratified into the Moderate Liver dysfunction Group (Group C) according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Because of these conditions, the patient was treated with metformin, levothyroxine, verapamil (120 mg bid), telmisartan, desloratadine, tramadol, fluticasone, paracetamol, and a curative dose of tinzaparin. Owing to this considerable polypharmacy, we asked the patient to participate in a prescribed oral chemotherapy program through collaborative consultation with a multidisciplinary group involving a doctor, a pharmacist, and a nurse.

During the pharmaceutical consultation, a suspected interaction between the moderate enzyme inhibitor, verapamil, and everolimus was noted. However, given the patient’s cardiac history, the prescription of verapamil was difficult to replace. Due to hepatic impairment and the risk of drug–drug interaction, the oncologist decided to prescribe everolimus at a reduced dosage of 7.5 mg instead of 10 mg per day, and to assess the trough blood concentration of everolimus at approximately 10 days after treatment initiation. The patient began everolimus treatment on 28 September and quickly developed canker sores and lingual edema, which were progressively aggravated. The patient consulted her general practitioner on 6 October, and began treatment with sodium bicarbonate, nystatin, amphotericin B, and lidocaine mouthwashes owing to grade 3 oral mucositis.

The toxicity test was performed on 9 October to investigate possible drug–drug interactions and everolimus trough blood concentration. Sampling was performed at 10:45 am when the last intake of the drug occurred on the previous day around noon. The electrochemiluminescence immunoassay (ECLIA) method supplied a residual everolimus plasma concentration of 52.4 ng/mL. Administration of everolimus was, however, suspended on 12 October due to both toxicological results and clinical side effects.

During the hospital consultation on 16 October, the patient still had grade 3 oral mucositis; however, the condition was significantly improved, and inflammation and canker sores were decreased. The oncologist proceeded to re-evaluate the symptomatic treatment, and proposed mouthwashes based on sodium bicarbonate, sucralfate, amitriptyline, lidocaine, and prednisolone. This treatment resulted in symptom improvement to grade 1 and facilitated the reintroduction of everolimus to a daily dose of 5 mg, beginning on 23 October. According to the examination performed during the scheduled consultation two days later, tolerance to treatment was indeed very good with slight increase in weight; this was despite the grade 1 oral mucositis.

During the first month of treatment, the patient experienced asthenia accentuated by recent weight loss; this resulted in social isolation and more repercussions for her daily life. Therefore, the psychological follow-up proposed at treatment initiation was continued. The efficacy of everolimus remained limited for more than one year, and a partial tumor response to the 5-mg dose was identified and deemed to be generally well tolerated.

Discussion

The interaction between verapamil–everolimus is referenced in the National Thesaurus of Drug Interactions, which was established by the French National Agency for Medicines and Health Products Safety (ANSM) as a “use with precaution” combination as an immunosuppressant. Therefore, it is recommended that the plasma concentrations of everolimus be monitored during and after its co-administration with verapamil for renal function control and subsequent dosage adjustment.⁴ This interaction is also mentioned in the European Medicines Agency summary of product characteristics (SPC) for AFINITOR®: “If patients require co-administration of a moderate CYP3A4 or P-glycoprotein (PgP) inhibitor, dose reduction of everolimus to 2.5 or 5 mg daily may be considered.” However, there are no clinical data that support this dose adjustment. Due to inter-individual variability in the efficacy and side effects of the drug, the recommended dose adjustments for everolimus may not be optimal for all patients; therefore, a close monitoring of side effects is recommended. If the moderate inhibitor is discontinued, a washout period of at least two to three days (the average elimination time for the most commonly used moderate inhibitors) may be considered before reinstating the everolimus dose used at the start of the co-administration.³ The US prescribing information differs slightly from the European version, as it recommends an initial dose of 2.5 mg and a subsequent increase to 5 mg upon observation of good tolerance.⁵ Lack of information regarding the SPC and differences between the SPC published by several countries limit the accurate detection of drug interactions.⁶

SPC of everolimus indicated that the area under the concentration-time curve (AUC) and the maximum blood plasma concentration (peak concentration) (C_max) of everolimus in the presence of verapamil increased by 3.5-fold (2.2–6.3) and 2.3-fold (1.3–3.8), respectively.³ The DDI-predictor website, which simulates AUC ratios with enzyme inhibitors or inducers, underestimated the AUC ratio (3.07; 1.75–5.37) by using the effect of the major cytochromes alone and not the drug transporters. However, this ratio considered a daily verapamil dose of 240 mg.⁷ The website also directed our attention to several points (Table 1).

Table 1.

Warnings regarding everolimus–verapamil interaction from the DDI-predictor website.

Warnings about the object drug (everolimus)	Warnings about the precipitant drug (verapamil)
Membrane transporters contribute significantly to the pharmacokinetics of this drug. The predicted AUC ratio might be inaccurate if the interacting drug inhibits or induces the functions of the involved transporters.	This interacting drug is a suicide inhibitor of CYP3A4. Inhibition vanishes gradually after the administration of the interacting drug is terminated. Subsequently, eight days are required for the return to basal CYP3A4 activity.
This drug has a low safety margin. An AUC ratio lower than 0.5 or greater than 2 may require a dosing readjustment or another intervention.
The elimination half-life of this drug or its active metabolite is greater than 48 h in the absence of drug–drug interaction. Hence, it may take several days to reach the predicted AUC ratio. By considering a gradual dosing adjustment, the impact of long-term coadministration on AUC ratio may be underrated.
The kinetics of this drug are nonlinear (the AUC is not proportional to the dose owing to saturable binding to red blood cells); therefore, the predicted AUC ratio might be inaccurate. Therapeutic drug monitoring (TDM) is, thus, recommended.

Two precedent case reports mentioned a drug–drug interaction between everolimus and an enzyme inducer (phenobarbital and fenofibrate).^8,9 Another case report revealed a possible interaction between everolimus and azole antifungals (fluconazole and voriconazole) based on their inhibitory potency for CYP3A4 activity.¹⁰ PgP inhibitors could also influence everolimus exposure, supporting the important role of this transporter in the metabolic clearance of everolimus and suggesting its role as a key target for drug interactions.¹¹ However, a meta-analysis by Ravaud et al.¹² found that the coadministration of everolimus with moderate CYP3A4 inhibitors did not affect the minimum blood plasma concentration (trough concentration) (C_min) of everolimus. Trough concentrations ranged from approximately 15 to 19 ng/mL at a standard daily dose of 10 mg. This did not exceed 22 ng/mL with PgP inhibitors, with which the highest plasma concentrations were identified.

Notably, the patient experienced moderate hepatic impairment. Previously, the AUC of everolimus in 8 subjects with Child-Pugh Class B was determined to be twice the amount in eight subjects with normal hepatic function; thus, the recommended dose for patients with moderate hepatic impairment was 5 mg daily.³

The above data supported the choice to start therapeutic drug monitoring (TDM), although contrary to CERTICAN®, TDM is not usually recommended for AFINITOR®. It is only recommended in the United States for tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, for the titration of the dosage necessary to attain trough concentrations between 5 ng/mL and 15 ng/mL. The recommended time points for everolimus whole blood trough concentration measurement are summarized in Table 2.

Table 2.

Recommended timing of everolimus TDM in tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures.

Event	When to assess trough concentrations after the event
Initiation of everolimus	1 to 2 Weeks
Modification of everolimus dose	1 to 2 Weeks
Initiation or discontinuation of PgP and the moderate CYP3A inhibitor	2 Weeks
Initiation or discontinuation of PgP and the strong CYP3A inducer	2 Weeks
Changes in hepatic function	2 Weeks
Stable dose with changing body surface area	Every 3 to 6 months
Stable dose with stable body surface area	Every 6 to 12 months

PgP: P-glycoprotein.

In France, the recommended pre-analytical conditions are only available for everolimus use as an immunosuppressant. These consist of assaying steady-state plasma concentrations at least two weeks after treatment initiation or any change in dosage to determine residual drug concentration (i.e. immediately before the intake of the subsequent dose). Other details, including the reason for prescription (efficacy or toxicity testing); time of collection; date of treatment initiation and/or possible dosage modification; dosing information (quantity administered, frequency, route of administration); and the age, height, and weight of the subject when acquirable, are required. Transport of the sample is performed after immediate freezing post-sampling (<4 h).¹³ Because these pre-analytical recommendations were followed for this patient, an analytical error was not suspected.

In our case, the dosage of everolimus (52.4 ng/mL) was determined by an ECLIA. This method, which is easier to use routinely, was sufficient to highlight an overdose; however, immunological methods are more sensitive to interference, including cross-reactions (sirolimus and everolimus metabolites).¹⁴ The preferred method for dosage determination is a fully validated liquid chromatography tandem mass spectrometry assay. Therefore, the choice of analytical method and differences between the approaches should be carefully considered when determining everolimus concentrations and comparing and interpreting clinical trial outcomes.¹⁵ In our case, the laboratory thresholds were 3.0 to 8.0 ng/mL when everolimus was used as an immunosuppressant and do not represent effective drug concentrations for use in oncology. Consequently, it is difficult to interpret the data even if at first glance an everolimus overdose that is related to enzymatic inhibition is conceivable. The plasmatic concentration only partially reflected the exposure to the drug, particularly if we consider the very large everolimus volume of distribution (i.e. 191 L in the apparent central compartment and 517 L in the apparent peripheral compartment). Approximately 20% of the everolimus concentration in cancer patients receiving 10 mg daily is found in plasma.³

A consensus report of everolimus TDM was published in 2016¹⁵ regarding its use in oncology; however, no recommendation for TDM was presented, warranting further investigations. Nevertheless, studies in patients with metastatic RCC revealed a median C_min of 14.1 ng/mL (range, 2.6–91.5 ng/mL). The only data currently available on everolimus TDM usage in oncology suggest that its plasma concentration should be between 11.9 ng/mL (threshold proposed for progression) and 26.3 ng/mL (threshold proposed for toxicity).¹⁶ However, the single-center observational study cited above only had 18.5% of patients with kidney cancer. Thus, further studies are required to confirm these findings. A meta-analysis found that 112 patients with RCC (63%) had everolimus plasma concentrations between 10 and 30 ng/mL. Additionally, it revealed the best median progression-free survival of 5.52 months (3.88–8.44).¹² When the previously defined thresholds were compared to the patient’s values, we found that the patient’s everolimus levels were twice the toxic threshold and 4.4 times the effective minimum threshold. In the same study, the most common grade 3–4 adverse events were blood, lymphatic system, and gastrointestinal disorders (especially mucositis), a finding consistent with the data from the SPC and the patient’s outcome.

A study concerning everolimus use in TSC-associated refractory seizures showed that the two-fold increase in C_min was not significantly associated with an increased risk of stomatitis or infections.¹⁷ However, if the therapeutic range recommended for this indication (5–15 ng/mL) is considered, the C_min of everolimus for the patient increased to between 3.5 and 10.5-fold. A past study showed that dose reduction and everolimus-induced stomatitis are strongly associated with the systemic exposure of patients with thyroid cancer to a daily dose of 10 mg everolimus.¹⁸

Later, the possible drug-to-drug interaction was examined. By considering the hepatic impairment and based on the Drug Interaction Suspicion Scale described in Table 3, the suspected everolimus–verapamil interaction was regarded as “probable.”²¹ If liver failure was considered to be an associated cause, the answer to question 7 was “No” and the score was reassessed to 7; however, this did not change the conclusion.

Table 3.

Assessment of the potential drug–drug interaction between verapamil and everolimus using the drug interaction probability scale.

Question	Answer	Score^a	Comments
1. Are there previous credible reports of this interaction in humans?	Yes	1	On healthy subjects.¹⁹
2. Is the observed interaction consistent with the known interaction properties of the precipitant drug?	Yes	1	Verapamil is a suicide inhibitor of CYP3A4.
3. Is the observed interaction consistent with the known interaction properties of the object drug?	Yes	1	Everolimus is extensively metabolized by CYP3A4. It is also a substrate of PgP
4. Is the event consistent with the known or reasonable time course of the interaction?	Yes	1	Verapamil enzymatic inhibition occurs immediately after the beginning of enzyme inhibition,²⁰ and inhibition vanishes gradually after the administration of the interacting drug is terminated. A return to basal CYP3A4 activity occurs in eight days.⁷ Verapamil is a PgP inhibitor.
5. Did the interaction remit upon dechallenge of the precipitant drug with no change in the object drug? (If there was no dechallenge, choose Unknown or Non-Applicable and skip question 6)	N/A	0	Verapamil was not interrupted
6. Did the interaction reappear when the precipitant drug was readministered in the presence of continued use of the object drug?	N/A	0	Verapamil was not interrupted
7. Are there reasonable alternative causes for the event?	Yes	–1	Moderate Hepatic impairment (Group C according to NCI-ODWG)
8. Was the object drug detected in the blood or other fluids in concentrations consistent with the proposed interaction?	Yes	1	Subtherapeutic trough concentration at J12
9. Was the drug interaction confirmed by any objective evidence consistent with the effects on the object drug (besides the drug concentrations from question 8)?	Yes	1	Grade 3 oral mucositis
10. Was the interaction greater when the precipitant drug dose was increased or reduced?	N/A	0	No verapamil dose adjustments were carried out
Total		5

CYP3A4: Cytochrome P450 3A4; PgP: P-glycoprotein; N/A: non-applicable; NCI-ODWG: National Cancer Institute Organ Dysfunction Working Group.

^aThe Drug Interaction Probability Scale assigns a probability category related to an adverse drug reaction to each score by using the following ranges: highly probable if the score is >8; probable, score of 5–8; possible, score of 2–4; doubtful, a score of <2.

Conclusion

The patient may have suffered the consequences of a drug–drug interaction, resulting in overexposure to everolimus. Because everolimus is a substrate for CYP3A4 and PgP, many inducers and inhibitors of these two proteins could be involved in its drug–drug interactions. This case report highlights the lack of clear recommendations for everolimus TDM in oncology for suboptimal patient care.

Dose adjustments based on everolimus TDM might be necessary in cases of possible overexposure based on the presence of drug interactions or adverse event reports. Indeed, several references previously confirmed the importance of everolimus TDM in oncology, as everolimus fulfils the prerequisites for TDM by possessing a narrow therapeutic range, high inter-individual pharmacokinetic variability, and an established drug exposure–response relationship.^15,18 Bayesian methods based on population pharmacokinetics modelling are emerging for predicting dose adjustments for several molecules, which are required to successfully manage individual therapies.²² Some tools, such as the Dosemerx.com website,²³ already offer pharmacokinetic estimations for everolimus as an immunosuppressant. Unfortunately, the potential benefit of precision dosing has not been clinically established for everolimus in oncology.²⁴

A twice-daily administration could be performed to increase tolerability in some cases via reductions in everolimus C_max without negative impacts on C_min or area under the concentration-time curve from 0 to 24 hours (AUC₂₄).²⁵ Innovative methods based on dried blood spots are emerging to facilitate the evaluation of everolimus plasma concentrations in oncology and stimulate interest in TDM.^26,27

Footnotes

Acknowledgements

The authors would like to thank the Oscar Lambret Center’s entire outpatient unit health care team. They also would like to be grateful to Prof. Michel Tod from Lyon University for allowing us to publish this case, for which the use of the DDI-predictor tool has helped us.

Authors’ contribution

GS, DP, IS, AV, FF, and GM wrote/edited the final version of the article. All authors read and approved the final version of the article.

Availability of data and material

The authors did not use any datasets, databases, or special software to write this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval and consent to participate

Ethical approval was not required for the present study. The authors obtained written consent from the patient prior to her participation in the study.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Geoffrey Strobbe

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