Journal
NUCLEIC ACID THERAPEUTICS
Volume 33, Issue 2, Pages 83-94Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/nat.2022.0054
Keywords
antisense oligonucleotide; drug metabolism; pharmacokinetics; biodistribution; bioanalysis
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Oligonucleotide therapeutics have become popular as a new treatment option for diseases that were previously difficult to target. However, there is a need to develop efficient methods for evaluating the metabolism and drug interactions of these therapeutics. The distribution and metabolism mechanisms of oligonucleotide therapeutics differ from small molecule drugs, and there are also challenges regarding experimental approaches in the evaluation of these therapeutics. This review summarizes the DMPK characteristics of antisense oligonucleotide (ASO) therapeutics and discusses how to optimize their evaluation and prediction.
Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional approaches. Technical advances in chemical modification and drug delivery systems have led to the generation of compounds with excellent profiles as pharmaceuticals, and 16 oligonucleotide therapeutics have been marketed to date. There is a growing need to develop optimal and efficient approaches to evaluate drug metabolism and pharmacokinetics (DMPK) and drug-drug interactions (DDIs) of oligonucleotide therapeutics. The DMPK/DDI profiles of small molecule drugs are highly diverse depending on their structural and physicochemical characteristics, whereas oligonucleotide therapeutics share similar DMPK profiles within each chemistry type. Most importantly, the mechanisms and molecules involved in the distribution and metabolism of oligonucleotides differ from those of small molecules. In addition, there are considerations regarding experimental approaches in the evaluation of oligonucleotides, such as bioanalytical challenges, the use of radiolabeled tracers, materials for in vitro metabolism/DDI studies, and methods to study biodistribution. In this review, we attempt to summarize the DMPK characteristics of antisense oligonucleotide (ASO) therapeutics and discuss some of the issues regarding how to optimize the evaluation and prediction of the DMPK and DDI of ASOs.
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