Absorption, distribution, metabolism, and excretion (ADME) are the key biological processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy and adverse drug reactions (ADRs). The chemical structures, dosage forms, and sites and routes of administration are the principal determinants of ADME profiles and consequent impacts on their efficacy and ADRs. Newly developed large biological antisense oligonucleotide (ASO) drugs have completely unique ADME that is not fully defined. ASO-based drugs are singlestranded synthetic antisense nucleic acids with diverse modes of drug actions from induction of mRNA degradation, exon skipping and restoration, and interactions with proteins. ASO drugs have a great potential to treat certain human diseases that have remained untreatable with small molecule-based drugs. The ADME of ASO drugs contributes to their unique set of ADRs and toxicity. In this review, to better understand their ADME, the ten FDA-approved ASO drugs were selected, including Fomivirsen, Pegaptanib, Mipomersen, Nusinersen, Inotersen, Defibrotide, Eteplirsen, Golodirsen, Viltolarsen, and Casimersen. A meta-analysis was conducted on their formulation, dosage, sites of administration, local and systematic distribution, metabolism, degradation, and excretion. Membrane permeabilization through endocytosis and nucleolytic degradation by endonucleases and exonucleases are major ADME features of the ASO drugs differing from small-molecule drugs. The information summarized here provides comprehensive ADME characteristics of FDA-approved ASO drugs, leading to a better understanding of their therapeutic efficacy and their potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distribution are identified, and future perspectives and directions are discussed.

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

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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.

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