Absorption, Distribution, Metabolism, and Excretion of FDA-approved Antisense Oligonucleotide Drugs.

Absorption, distribution, metabolism, and excretion (ADME) are key biological processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on therapeutic efficacy and adverse drug reactions (ADRs). Drug structures, formulations, and administration sites and routes cause different classes of drugs to have various ADME characteristics and consequent impacts upon efficacy and ADRs. For example, orally administered small molecule drugs are usually absorbed and distributed by uptake transporters, biotransformed by phase I/II drug-metabolizing enzymes, and excreted by efflux transporters. However, newly developed large molecule biological drugs, including antisense oligonucleotide (ASO) drugs, have substantially different ADME parameters. ASO drugs are single-stranded antisense nucleic acids with diverse modes of drug action that induce mRNA degradation, exon skipping, and ASO-protein interactions. ASOs have a great potential to treat certain human diseases that have not been treatable with small molecule drugs. The ADME behaviors of ASO drugs contribute to their unique set of ADRs and toxicity. To better understand their ADME features, ten FDA-approved ASO drugs were selected, including Fomivirsen, Pegaptanib, Nusinersen, Mipomersen, Inotersen, Defibrotide, Eteplirsen, Golodirsen, Viltolarsen, and Casimersen. A comprehensive meta-analysis was conducted on their formulation, dosage, sites of administration, local and systematic distribution, metabolism, degradation, and excretion. Membrane permeabilization and nucleotide degradation by endonucleases and exonucleases are major contributors to ADME features of the ASO drugs and these differ from the roles of transporters and metabolizing enzymes of small molecule drugs. The summarized information provides the most updated knowledge of ADME characteristics of these ASO drugs, leading to a better understanding of their therapeutic efficacy and potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distributions are identified and future perspective and directions are discussed.