Davis, John, Kulmatycki, Ken, Humphries, Sara C, Iqbal, Sajida, Kamel, Amin, Lao, Yanbin, Liu, Xiumin, Rogers , John, Snoeys, Jan, Weng, Yan, Vigil, Adam, Wiethoft, Christopher M and Wittwer, Matthias B (2022) Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics. Nucleic acids research, 50 (11). pp. 6020-6037.

Abstract

At the time of writing, although four siRNA therapeutics have been approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule (ICH M3(R2)) and biologics (ICH S6(R1)) guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in both its physicochemical and absorption, distribution, metabolism and excretion (ADME) properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the ‘siRNA plasma protein binding and drug-drug interaction working group’ in the IQ consortium discuss the relevance of two such reports---the plasma protein binding (PPB) evaluation and the drug-drug interaction (DDI) risk assessment---to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA PPB and DDIs in ADME, safety and translation. This information has been summarized into two decision trees to help guide industry to decide when siRNA PPB and DDI studies are warranted.

Item Type:	Article
Keywords:	None
Date Deposited:	21 Jul 2022 00:45
Last Modified:	21 Jul 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45727