Assessment of in vitro inhibition of CYPs, UGTs and transporters by oligonucleotides

Assessment of in vitro inhibition of CYPs, UGTs and transporters by oligonucleotides

Published:  5/28/2019 8:00:00 AM

An assessment of the in vitro inhibition of cytochrome P450 enzymes (CYP), UDP-glucuronsyltransferases (UGT) and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides

Presented at the 2019 Marbach Castle Drug-Drug Interaction Workshop in Germany
Dr. Brian W. Ogilvie
Sekisui XenoTech, LLC, Kansas City, KS, USA
Based on the publication: Kazmi F, Yerino P, McCoy C, Parkinson A, Buckley DB, Ogilvie BW. (2018) Oligonucleotide Inhibition of P450s, UGTs, and Transporters. Drug Metab Dispos 46:1066-1074.

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:  
Abstract:
Regulatory guidance documents do not have specific recommendations for ASO DDI evaluation, but these molecules do fall under the scope of overall DDI testing.
 
Aims:
  1. Evaluate different ASOs as inhibitors of CYPs, UGTs and transporters in vitro.
  2. Determine if in vitro inhibition of CYPs and UGTs in HLM by phosphorothioate ASOs is an artefact not observed in CHH...

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