@article {Ramsdendmd.119.087098, author = {Diane Ramsden and Jing-Tao Wu and Brad Zerler and Sajida Iqbal and Jim Jiang and Valerie Clausen and Krishna Aluri and Yongli Gu and Sean Dennin and Joohwan Kim and Saeho Chong}, title = {In Vitro Drug-Drug Interaction Evaluation of GalNAc conjugated siRNAs Against CYP450 Enzymes and Transporters}, elocation-id = {dmd.119.087098}, year = {2019}, doi = {10.1124/dmd.119.087098}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Small interfering RNAs (siRNAs) represent a new class of medicines that are smaller (~16,000 Da) than biological therapeutics (\>150,000 Da) but much larger than small molecules (\<900 Da). Current regulatory guidance on drug-drug interaction (DDI) from EMA, FDA, and PMDA provide no recommendations for oligonucleotide therapeutics including siRNAs, therefore small molecule guidance documents have historically been applied. Over ~10 years, in vitro DDI investigations with siRNAs conjugated to a triantennary N-acetylgalactosamine ligand (GalNAc-siRNAs) have been conducted during nonclinical drug development to elucidate the potential clinical DDI liability. GalNAc-siRNAs were evaluated as substrates, inhibitors or inducers of major CYPs and as substrates and inhibitors of transporters. Aggregate analysis of these data demonstrates a low potential for DDI against CYPs. Zero of five, ten and seven are inducers, time-dependent inhibitors, or substrates, respectively, and 9 of 12 do not inhibit any CYP isoform evaluated. Three GalNAc-siRNAs inhibited CYP2C8 at supratherapeutic concentrations, and one mildly inhibited CYP2B6. The lowest Ki of 28 {\textmu}M is \>3000-fold above the therapeutic clinical Cmax,ss and importantly no clinical inhibition was projected. Of four GalNAc siRNAs tested none were substrates for transporters and one caused inhibition of P-gp, calculated not to be clinically relevant. Pharmacological basis for DDI, including consideration of the target and/or off-target profile for GalNAc-siRNAs should be made as part of the overall DDI risk assessment. If modulation of the target protein doesn{\textquoteright}t interfere with CYPs or transporters, then in vitro or clinical investigations into the DDI potential of the GalNAc-siRNAs are not warranted.SIGNIFICANCE STATEMENT Recommendations for evaluating DDI potential of small molecule drugs are well established, however guidance for novel modalities, particularly oligonucleotide-based therapeutics are lacking. Given the paucity of published data in this field in vitro DDI investigations are often conducted. The aggregate analysis of GalNAc-siRNA data reviewed herein demonstrates that like new biological entities (NBEs), these oligonucleotide-based therapeutics are unlikely to result in DDI, and therefore it is recommended that the need for in vitro or clinical investigations similarly be determined on a case-by-case basis. Given the mechanism of siRNA action, special consideration should be made in cases where there may be a pharmacological basis for DDI.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2019/07/03/dmd.119.087098}, eprint = {https://dmd.aspetjournals.org/content/early/2019/07/03/dmd.119.087098.full.pdf}, journal = {Drug Metabolism and Disposition} }