PT - JOURNAL ARTICLE AU - Diane Ramsden AU - Jing-Tao Wu AU - Brad Zerler AU - Sajida Iqbal AU - Jim Jiang AU - Valerie Clausen AU - Krishna Aluri AU - Yongli Gu AU - Sean Dennin AU - Joohwan Kim AU - Saeho Chong TI - In Vitro Drug-Drug Interaction Evaluation of GalNAc conjugated siRNAs Against CYP450 Enzymes and Transporters AID - 10.1124/dmd.119.087098 DP - 2019 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.119.087098 4099 - http://dmd.aspetjournals.org/content/early/2019/07/03/dmd.119.087098.short 4100 - http://dmd.aspetjournals.org/content/early/2019/07/03/dmd.119.087098.full AB - 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 µM 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'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.