In Vitro Drug-Drug Interaction Evaluation of GalNAc conjugated siRNAs Against CYP450 Enzymes and Transporters

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 ( 3000-fold above the therapeutic clinical C max,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 doesn9t 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.