Abstract
Background: Antisense oligonucleotide (ASO), an emerging modality in drug research and development, demands accurate and sensitive bioanalysis to understand its pharmacokinetic and pharmacodynamic properties. Results: By combining theadvantages of both ligand binding and liquid chromatography-mass spectrometry/tandem mass (LC-MS/MS), hybridization LC-MS/MS methods were successfully developed and validated/qualified in a good lab practice (GLP) environment for the quantitation of an ASO drug candidate in monkey serum, cerebrospinal fluid (CSF)and tissues in the range of 0.5-500ng/ml. Special treatment of CSF samples was employed to mitigate nonspecific binding, improve long-term storage stabilityand enable the usage of artificial CSF as a more accessible surrogate matrix. The method was also qualified and applied to ASO quantitation in various monkey tissue samplesusing a cocktail tissue homogenate as a surrogate matrix. Conclusion: This work was the first reported GLP validation and application of ASO bioanalysis using the hybridization LC-MS/MS platform.
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