https://orcid.org/0000-0001-9193-5845
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Abstract
Aim: Mass-selective quantitation is a powerful attribute of LC–MS as a platform for bioanalysis. Here, a sensitive LC–MS approach has been validated for an oligonucleotide having chemical modifications (e.g., N-acetylgalactosamine [GalNAc] conjugated), to distinguish between the conjugated and unconjugated forms of the oligonucleotide, thereby enabling a nuanced view of the pharmacokinetic profile. Results: A high-sensitivity methodology for mass-specific measurement of AZD8233, a GalNAc-conjugated 16-mer oligonucleotide, using LLE-SPE with optimized LC conditions and detection of a low-mass fragment ion was successfully validated in the range of 0.20–100ng/ml in human plasma. Conclusion: The AZD8233 LC–MS methodology adds valuable insight on the GalNAc linker’s in vivo stability to the program and should be broadly applicable to oligonucleotides requiring high sensitivity and mass-selective measurement for quantitative discrimination from metabolites and endogenous interferences.
Acknowledgments
A Dahlén, Oligonucleotide Chemistry, AstraZeneca, is acknowledged for his support with ISTD generation and characterization.
Financial & competing interests disclosure
AR Ledvina, M Ewles, P Severin and D Good are all Covance employees and may hold stocks in Covance. C Arfvidsson is AstraZeneca employee and may hold stocks in AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: https://www.tandfonline.com/doi/suppl/10.2144/000112170