title: 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.
authors.affiliation: Departments of Oncology, University Hospital Amiens, Amiens, France ; Departments of Rheumatology, University Hospital Amiens, Amiens, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Séjourné
authors.affiliation: Department of Oncology, F. Baclesse Center for the Fight against Cancer, Caen, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Noal
authors.affiliation: Departments of Oncology, University Hospital Amiens, Amiens, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boone
authors.affiliation: Departments of Oncology, University Hospital Amiens, Amiens, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bihan
authors.affiliation: Department of Oncology, F. Baclesse Center for the Fight against Cancer, Caen, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Sassier
authors.affiliation: Departments of Clinical Pharmacology, University Hospital Amiens, Amiens, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Andrejak
authors.affiliation: Departments of Oncology, University Hospital Amiens, Amiens, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
keywords: Aprepitant; Drug interaction; Encephalopathy; Ifosfamide