Two Cases of Fatal Encephalopathy Related to Ifosfamide: An Adverse Role of Aprepitant

Abstract

Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT₃ antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.

Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists

“…Both aprepitant and netupitant can inhibit cytochrome P-450 isoenzyme 3A4 (CYP3A4), and a reduced dose of dexamethasone (CYP3A4 substrate) should be administered with aprepitant and NEPA. Additionally, aprepitant is a CYP3A4 inducer and has the potential to increase ifosfamide-mediated neurotoxicity [70]. No increased toxicities have been reported to date related to NEPA interaction with chemotherapeutic agents [71, 72].…”

Aprepitant and fosaprepitant drug interactions: a systematic review

“…The interaction between aprepitant and ifosfamide was a probable cause of neurotoxicity in one of the nine case reports (DIPS: 6) . Neurotoxicity was unlikely to be due to an interaction between ifosfamide and aprepitant/fosaprepitant in the remaining case reports (DIPS: <5) . Results from the retrospective studies, four specifically evaluating the co‐administration of ifosfamide IV with aprepitant/fosaprepitant and two evaluating general risk factors for ifosfamide‐induced neurotoxicity , did not demonstrate an increased likelihood of ifosfamide‐induced neurotoxicity or encephalopathy in the presence of aprepitant/fosaprepitant.…”

“…Thirteen publications (six retrospective studies, nine case reports and one case series) evaluated neurotoxicity associated with the combination of ifosfamide and aprepitant/fosaprepitant. The interaction between aprepitant and ifosfamide was a probable cause of neurotoxicity in one of the nine case reports (DIPS: 6) .…”

“…Reports of the interaction between ifosfamide and aprepitant/fosaprepitant were also conflicting. While case reports [23,59,65,66,72] attributed ifosfamide-induced neurotoxicity to an aprepitant-ifosfamide drug interaction, only one case report had a DIPS score that would suggest that the interaction was the probable cause (DIPS score: 6) [23]. The included retrospective studies did not report P-values or demonstrate a statistically significant difference in ifosfamide-induced neurotoxicity rates in the presence of aprepitant [54,57,58,67,69,70].…”

“…Antineoplastic drugs. Twenty-four included publications reported adverse events attributed to co-administration of aprepitant or fosaprepitant and an antineoplastic agent (anthracyclines, bexarotene PO, dinaciclib IV, erlotinib, ifosfamide IV, and pazopanib IV) [23,25,33,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]72]. Of these, interactions between fosaprepitant and anthracyclines and aprepitant and ifosfamide IV were the suspected cause.…”