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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.

Original publication

DOI

10.1053/j.ajkd.2010.09.024

Type

Journal article

Journal

Am J Kidney Dis

Publication Date

02/2011

Volume

57

Pages

300 - 303

Keywords

Acute Kidney Injury, Dose-Response Relationship, Drug, Eye Neoplasms, Humans, Inhibitor of Apoptosis Proteins, Liver Neoplasms, Lung Neoplasms, Male, Melanoma, Microtubule-Associated Proteins, Middle Aged, Oligonucleotides, Oligonucleotides, Antisense, RNA, Messenger, Treatment Outcome