An assessment of in vitro inhibition of CYPs, UGTs and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides
Presented at the 2019 Marbach Castle Drug-Drug Interaction Workshop in Germany by Dr. Brian W. Ogilvie.
The poster presented information based on the publication:
What is already known about this subject?
- Antisense oligonucleotides (ASOs) are increasingly being developed for many indications and are often modified with phosphorothioate linkages in lieu of phosphodiester linkages.
- Few in vitro DDI studies with ASOs have been performed, including the investigational imetelstat, volanesorsen, and ISIS 681257.
- No clinical DDIs have been reported.
What this study adds:
- This study evaluated the inhibitory effects of two non‑therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages on the major drug-metabolizing CYPs and UGTs in both human liver microsomes (HLM) and cryopreserved Human hepatocytes (CHH), and toward select transporters in expression systems.
Regulatory guidance documents do not have specific recommendations for ASO DDI evaluation, but these molecules do fall under the scope of overall DDI testing.
This study aims to:
- Evaluate different ASOs as inhibitors of CYPs, UGTs and transporters in vitro.
- Determine if in vitro inhibition of CYPs and UGTs in HLM by phosphorothioate ASOs is an artefact not observed in CHH…