Drug Metabolism, Pharmacokinetics, and Bioanalytical Strategies for Small Molecules and Oligonucleotide Therapeutics

Drug metabolism and pharmacokinetics (DMPK) research forms a cornerstone of modern drug discovery and development. Traditionally, small molecules and monoclonal antibodies have dominated the therapeutic landscape; however, these modalities have limitations in addressing numerous disease-relevant targets considered “undruggable.” The advent of oligonucleotide therapeutics, particularly small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), has revolutionized drug design by enabling targeted modulation at the mRNA level. This has significantly expanded the diversity of druggable targets and accelerated the pursuit of precision medicine. Despite these advances, the distinct physicochemical, metabolic, and distributional characteristics of oligonucleotides compared to small molecules create unique challenges that necessitate the development of specialized DMPK and bioanalytical approaches. The field continues to evolve toward addressing these complexities, including the integration of advanced analytical technologies, improved predictive models, and regulatory frameworks to support safer and more effective therapeutics.This Research Topic aims to foster scientific exchange and highlight recent progress in drug metabolism, pharmacokinetics, and bioanalytical sciences applied to small molecules and oligonucleotide therapeutics. It seeks to bring together innovative methodologies, mechanistic insights, and regulatory perspectives that advance our understanding of drug absorption, distribution, metabolism, and excretion (ADME), thereby optimizing drug design, safety, and efficacy. Contributions are encouraged that explore emerging strategies for the quantitative and qualitative characterization of drugs in biological systems, with an emphasis on translational relevance and the harmonization of regulatory practices across therapeutic classes.To gather further insights into technologies and strategies that enable drug discovery across small molecules and oligonucleotide therapeutics, we welcome articles addressing, but not limited to, the following themes:&#8226 Physicochemical characterization of drug candidates, including solubility, stability, lipophilicity, and formulation-related properties&#8226 In vitro ADME studies: metabolic stability, permeability, protein binding, transporter interactions, enzyme phenotyping, and drug-drug interaction studies using innovative methods such as cocktail approaches and tissue slice binding assays&#8226 Overcoming challenges in ADME assay optimization, including issues related to non-specific binding and compound stability&#8226 New approaches for characterizing clearance mechanisms in low-turnover compounds&#8226 Use of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modeling&#8226 In vivo pharmacokinetic (PK), toxicokinetic (TK), tissue distribution, and PK/PD relationship studies&#8226 Innovations in bioanalytical technologies for quantifying small molecules and oligonucleotides in complex biological matrices&#8226 Method development and validation using LC–MS/MS and high-resolution mass spectrometry for multi-matrix bioanalysis&#8226 Analytical advancements for metabolite identification in next-generation oligonucleotide modalities, including GalNAc-siRNAs and antibody–oligonucleotide conjugates (AOCs)&#8226 Case studies, regulatory challenges, and best practices in ADME, DMPK, and bioanalytical method applications Topic editors: Xiaoqing Sarah Wu, Sandhya Rani Chennupati, Ravi Akkireddy Source: https://www.frontiersin.org/research-topics/83159/drug-metabolism-pharmacokinetics-and-bioanalytical-strategies-for-small-molecules-and-oligonucleotide-therapeutics