Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study

Abstract

BackgroundPatients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.Case presentationOn Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.ConclusionsAfter extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.

Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

“…Lethal hepatotoxicity was reported in a patient concurrently receiving intravenous fenretinide and ceftriaxone (49). Excluding coadministration of ceftriaxone, which causes biliary sludging in some patients, enables intravenous fenretinide to be safely administered without hepatotoxicity.…”

Predictors of response, progression‐free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high‐risk neuroblastoma

“…A retrospective review was performed of patients enrolled on 13 NANT therapeutic trials from March 1, 2000 (first NANT enrollment) through October 19, 2009 (per Institutional Review Board [IRB] cutoff date). Trials utilized MIBG‐based therapy with peripheral blood stem cell (PBSC) support (n = 5), or novel agents ± chemotherapy with PBSC support (n = 2) or without PBSC support (n = 6) (Supplementary Table S1).…”

Analysis of fenretinide and its metabolites in human plasma by liquid chromatography–tandem mass spectrometry and its application to clinical pharmacokinetics

“…The validated method was applied to PK samples from a phase I clinical trial of 4-HPR conducted in the New Approaches to Neuroblastoma Therapy (NANT) consortium (NANT 2004-03) [29]. The study was approved by the Institutional Review Board at each site where patients provided blood samples for PK and by the Texas Tech University Health Sciences Center (TTUHSC), Lubbock, Texas.…”