ADME considerations for siRNA-based therapeutics

After almost three decades, the utilization of RNA interference (RNAi) to defeat disease has become a reality. Multiple modalities have emerged that exploit the endogenous RNAi pathways. One approach is small interfering RNAs (siRNA) that engage the RNA-induced silencing complex to silence complementary endogenous RNA targets such as mRNA, halting protein synthesis. The emerging modality of siRNA will be the topic of this review chapter. With new drug modalities, there becomes a need to develop new assays to understand the absorption, distribution, metabolism, and excretion properties. Here, we examine tools critical to the development of oligonucleotide drugs and discuss their applicability to the translational development of new chemical entities. Our aim is to review the current practices of the field and to highlight areas of possible improvement.