A Case of Encephalopathy Caused by Drug Interaction between Ifosfamide and Aprepitant

Summary

A 72-year-old man with a malignant retroperitoneal soft tissue tumor was treated with ifosfamide (IFO) for 5 consecutive days (1.8 g/m²/d×5 d, expected dose 9 g/m²). The patient developed neurological symptoms such as mild somnolence, seizures, and inability to write from Day 1, and became delirious on Day 3, so IFO was discontinued on Day 4 (dose: 7.2 g/m²). Since there are reports of drug interactions that increase the frequency of encephalopathy when combined with aprepitant (Apr), Dexamethasone was increased and IFO was administered without the use of Apr after the second course, and there was no recurrence of encephalopathy in the second and third courses. IFO-induced encephalopathy is considered to occur due to an increase in blood concentration of IFOs caused by high dosage, decreased renal function, or other factors. In this case, encephalopathy was observed even though the dose of IFO was reduced due to the patient’s advanced age and impaired renal function. The combination use of Apr with IFO should be considered with caution for the occurrence of adverse events, including encephalopathy, and if possible, control of gastrointestinal toxicity with other antiemetic agents should be considered.

INTRODUCTION

Ifosfamide (IFO) is an alkylating agent of the oxazaphosphorine family. In Japan, ifosfamide is used as one of the key drugs for malignant bone and soft tissue tumors after the indication was added in 2005.^1,2) IFO is believed to exert its antitumor effect through its active metabolites, 4-hydroxyifosfamide and aldoifosfamide, which are converted by metabolic enzymes in the liver and excreted through the kidneys.

Encephalopathy,³⁾ one of the most problematic adverse events in IFO administration, is a neurological symptom caused by several metabolites and is more likely to occur when there is an increase in blood levels of metabolites^2,4,5) due to high doses, reduced renal function, or other factors.^6–9)

The neurokinin 1 (NK1) receptor activates various signaling pathways by binding to substance P.

Among chemotherapy induced nausea and vomiting (CINV), delayed onset vomiting, which occurs 24 h or later after anticancer drug administration, is caused by the binding of substance P to NK1 receptors in the nucleus accumbens and vagal nerve endings of the intestinal tract. Therefore, NK1 receptor antagonists have antiemetic effects.

IFOs are classified as moderate to high risk for CINV in guidelines published by several societies, and the use of NK 1 receptor antagonists as antiemetic agents is recommended or optional (Table 1).

Table 1. Ifosfamide Emetogenic Risk Classification in Various Guidelines

Society/Group	JSCO		NCCN		ASCO	ESMO, MASCC
Year	2015		2021		2020	2016
Emetic-risk	≧2 g/m2 per dose	High	≧2 g/m2 per dose	High	Moderate	Moderate
	<2 g/m2 per dose	Moderate	<2 g/m2 per dose	Moderate

JSCO: Japan Society of Clinical Oncology, NCCN: National Comprehensive Cancer Network, ASCO: American Society of Clinical Oncology, ESMO: European Society for Medical Oncology, MASCC: Multinational Association of Supportive Care in Cancer.

Aprepitant (Apr), an NK 1 receptor antagonist, both induces and inhibits the metabolic enzyme CYP3A4 and has been reported to interact with a variety of drugs.¹⁰⁾

Although it has been reported that concomitant administration of IFO, which is metabolized by CYP3A4, with NK 1 receptor antagonists may exacerbate or increase the risk of neurological symptoms that may be considered encephalopathy due to drug interactions,^11–15) the package insert has not yet been revised.

CASE PRESENTATION

The patient was a 72-year-old male, history: hypertension, current medical history: he had been aware of pain in his right scrotum since 2 months before, and was referred to our hospital with suspicion of malignant soft-tissue tumor, as computed tomography (CT) showed pelvic tumor and bone destruction of the iliac bone.

The pathological review revealed a diagnosis of high-grade spindle cell sarcoma, and chemotherapy was planned since surgery was not indicated due to bone invasion and other reasons. Right hydronephrosis was caused by compression of the tumor in the pelvis.

The tumor was planned to be treated with IFO alone regimen [1.8 g/m²/d×5 d, expected dose 9 g/m² (Table 2)].

Table 2. Ifosfamide Regimen

Course 1	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6
Ifosfamide (g)	2.8	2.8	2.8	2.8	✕	—	Total 11.2 g
Aprepitant (mg)	125	80	80	✕	✕	—
Granisetron (mg)	1	1	1	1	1	—
Dexamethasone (mg)	3.3	3.3	3.3	3.3	3.3	—
Granisetron (mg)	1	1	1	1	1	1
Course 2, 3	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6
Ifosfamide (g)	2.4	2.4	2.4	2.4	2.4	—	Total 12.0 g
Aprepitant (mg)	—	—	—	—	—	—
Granisetron (mg)	1	1	1	1	1	—
Dexamethasone (mg)	6.6	6.6	6.6	6.6	6.6	—
Granisetron (mg)	1	1	1	1	1	3

Body surface area at the beginning of treatment was 1.61 m²．

For antiemetic therapy, we decided to use three drugs, Apr, granisetron, and dexamethasone (Dex), based on the antiemetic guidelines published by several academic societies, and planned to use Apr from Day 1 to 5 since IFO is administered for 5 d.

The patient developed somnolence on Day 1 and could not stay awake during the day; somnolence continued during the day on Day 2, and on Day 3, encephalopathy, Grade 3 on the Common Terminology Criteria for Adverse Events (CTCAE) Ver 5.0, including seizures and inability to write, occurred. The delirium score using the Nursing Delirium Screening Scale (NDSS) was 10 (Table 3).

Table 3. Nursing Delirium Screening Scale

Nursing Delirium Screening Scale
Symptoms Rating (0–2)
0. No symptoms
1. Mild symptoms
2. Obvious symptom
Symptom
1. Disorientation
Verbal or behavioural manifestation of not being oriented to time or place or misperceiving persons in the environment.
2. Inappropriate behaviour
Behaviour inappropriate to place and/or for the person; e.g., pulling at tubes or dressings, attempting to get out of bed when that is contraindicated, and the like.
3. Inappropriate communication
Communication inappropriate to place and/or for the person; e.g., incoherence,noncommunicativeness, nonsensical or unintelligible speech.
4. Illusions/Hallucinations
Seeing or hearing things that are not there; distortions of visual objects.
5. Psychomotor retardation
Delayed responsiveness, few or no spontaneous actions/words; e.g., when the patient is prodded, reaction is deferred and/or the patient is unarousable.
Total score (0–10)

Because IFOs are known to cause neurological symptoms, they were administered through Day 4 and discontinued on Day 5.

Since no gastrointestinal toxicity such as vomiting or nausea was observed, it was determined that the dose of the antiemetic could be reduced. To avoid drug interactions between the antiemetic, Apr, and IFO, Apr was discontinued on Days 4–5.

After discontinuation of IFO, delirium gradually improved, and by Day 11, the NDSS score was 3, with Grade 0 encephalopathy (Fig. 1).

Fig. 1. Renal Function and Delirium Score

#1: First course of IFO administration, #2: second course of IFO administration, #3: third course of IFO administration, △: delirium score, ■: estimated glomerular filtration rate, 〇: serum creatinine.

Imaging evaluation showed that IFO was effective against the tumor and a second course was to be administered.

Because of the mild gastrointestinal toxicity of the first course and the suspected drug–drug interaction as an exacerbating factor for encephalopathy, Apr was not used.

As an alternative, antiemetic therapy was handled by increasing the dose of Dex.

The second course passed with encephalopathy Grade 0 and gastrointestinal toxicity Grade 0, and the patient was discharged without problems. The third course was treated with the same IFO regimen and antiemetic therapy as the second course, but the patient was discharged with delirium, encephalopathy Grade 0, and gastrointestinal toxicity Grade 0.

Serum creatinine level was 0.94 mg/dL before the second course and 1.20 mg/dL before the third course, and renal dysfunction remained in Grade 0–1 from before administration to the end of the third course.

After three courses of IFO administration, tumor growth was observed and the treatment became ineffective, so the patient was switched to another treatment method, which was not used thereafter. The patient had Grade 1 hypoalbuminemia prior to the start of IFO administration, but there was no change in Grade during the treatment period. There were no medications used in combination with IFOs or drugs that interacted with Apr, and hydronephrosis did not improve after the treatment period.

DISCUSSION

In this case, IFO was one of the key drugs for the treatment of the tumor, and the choice of drugs to be administered was limited. When the patient showed a tendency toward somnolence after the start of treatment, we did not consider it to be related to IFO, because the symptoms were initially minor. However, the onset and prolongation of somnolence during the day after Day 2 led us to suspect neurological symptoms.

Since metabolites of IFO administration include 2- and 3-dechloroethylifosfamide^2,4) and S-carboxymethylcysteine,⁵⁾ which are known to cause neurological symptoms, we hypothesized that they had some influence on the development of neurological symptoms in this case. In addition, drug–drug interactions with Apr were considered as a factor that may exacerbate the neurological symptoms. There have been many reports on risk factors for the occurrence of neurological symptoms during IFO administration,^11–15) including renal dysfunction and high-dose IFO administration, and drug interactions with NK1 receptor antagonists have also been reported to exacerbate symptoms or increase the risk for the occurrence of symptoms. The risk of developing symptoms is also reported to be exacerbated or increased by drug interactions with NK 1 receptor antagonists.

The NK 1 receptor antagonist Apr inhibits the metabolic enzyme CYP3A4,¹⁶⁾ and methylprednisolone¹⁷⁾ and midazolam,¹⁸⁾ which are metabolized by CYP3A4, are known to increase area under the curve (AUC) 2.1- to 3.3-fold, respectively, when combined with Apr.

These same increases in blood concentrations of active metabolites of IFO, which are metabolized by CYP3A4, would also increase blood concentrations of metabolites that cause neurological symptoms as well as decreased elimination due to renal dysfunction and increased metabolites due to high doses of the drug.

In this case, encephalopathy was observed despite a reduction in the dose of IFO from the first course due to renal dysfunction, which may have been caused by delayed excretion of metabolites of IFO, and concomitant use of Apr may have contributed to increased blood concentrations of metabolites.

Because this patient had a rare cancer and there were only a limited number of other anticancer drugs that could be considered effective, IFO treatment was continued even after the onset of neurological symptoms. After the onset of neurological symptoms, treatment with IFOs was continued, and no encephalopathy was observed during the second and third courses when the combination of Apr was discontinued, despite the higher total dose of IFOs administered in the first course.

We believe that this case is an important report in that it clearly demonstrates the interaction of IFO and Apr in combination, as there was a significant difference in the occurrence of neurological symptoms in the same patient with and without the combination of IFO and Apr.

Based on the above, the occurrence of IFO encephalopathy in this case is considered to be caused by drug interaction due to concomitant use of Apr.

A limitation of this report is that blood levels of IFOs and metabolites thought to cause neurologic symptoms were not measured, and thus do not prove drug interactions, but rather reports in clinical symptoms.

IFOs are classified as a moderate-to-severe emetogenic risk by several medical societies, and concomitant use of Apr as an antiemetic agent is either recommended or optional. However, there is no effective treatment for the development of IFO encephalopathy, and it is desirable to avoid the development of IFO encephalopathy.

In light of this case and previous reports, we believe that when Apr is used as an antiemetic agent in combination with IFO monotherapy, the occurrence of adverse events, including encephalopathy, should be carefully monitored and control with other antiemetic agents should be considered.

Acknowledgements

We thank both the Pharmacy and Department of Musculoskeletal Oncology and Rehabilitation Medicine National Cancer Center Hospital.

Conflict of Interest

The authors declare no conflict of interest.

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