title: Association of long-term administration of the survivin mRNA-targeted antisense oligonucleotide LY2181308 with reversible kidney injury in a patient with metastatic melanoma.
abstract: A 57-year-old man with metastatic melanoma was treated with the survivin inhibitor and antisense oligonucleotide LY2181308 as part of a First-in-Human Dose trial. After 18 months of treatment, he developed kidney injury and the treatment was discontinued. At 9 months and before the development of kidney injury, LY2181308 concentrations were 8- to 10-fold higher relative to median predicted values, but within the targeted exposure considered to be safe. However, at 17 months, 28 days after stopping LY2181308 therapy, LY2181308 concentration exceeded the predicted range by 38-fold. His decreased kidney function was slow to improve after stopping treatment. A kidney biopsy showed signs of acute tubular injury with regeneration. Complete recovery of kidney function occurred 6 months after treatment was stopped. The relationship between high exposures and slow LY2181308 clearance with the gradual improvement in kidney function after stopping the antisense treatment suggests that the oligonucleotide was related to the kidney injury. Based on this case report, kidney function should be monitored frequently in patients receiving long-term treatment with antisense oligonucleotides that specifically target survivin, particularly when they receive concomitant angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.
authors.affiliation: Churchill Hospital, Oxford, UK. w.herrington@doctors.org.uk
authors.forename: William G
authors.initials: WG
authors.lastname: Herrington
authors.forename: Denis C
authors.initials: DC
authors.lastname: Talbot
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.forename: John T
authors.initials: JT
authors.lastname: Brandt
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.forename: Ray
authors.initials: R
authors.lastname: Nagle
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Winearls
authors.forename: Ian S D
authors.initials: IS
authors.lastname: Roberts
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000175:diagnosis; D004305:Dose-Response Relationship, Drug; D005134:Eye Neoplasms / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008875:Middle Aged; D009841:Oligonucleotides / Q000009:adverse effects* / Q000627:therapeutic use; D016376:Oligonucleotides, Antisense / Q000009:adverse effects* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077022:Survivin; D016896:Treatment Outcome
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C529350:LY 2181308; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000077022:Survivin