{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:45:23Z","timestamp":1792133123077,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Unconjugated antisense oligonucleotides (ASOs) and GalNAc\u2010conjugated small interfering RNAs (siRNAs) have emerged as transformative therapeutic modalities, but their translation remains hindered by complex pharmacokinetics characterized by rapid plasma clearance, heterogeneous tissue uptake, and prolonged intracellular retention. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic framework to integrate these processes across species, yet applications to oligonucleotides remain limited, and existing efforts are typically restricted to specific chemistries or routes of administration. This study aimed to develop a cross\u2010species PBPK platform to characterize the plasma and tissue disposition of unconjugated ASOs and GalNAc\u2010siRNAs in preclinical species and humans, and to evaluate the consistency of estimated drug\u2010specific parameters with pre\u2010specified allometric scaling relationships within the domain of compounds and routes considered. Published datasets spanning mice, rats, non\u2010human primates, and humans were integrated for representative unconjugated ASOs (Malat\u20101, GluR1, p\u2010tau, tominersen) and GalNAc\u2010siRNAs (ALN\u2010AT3, givosiran, fitusiran). The PBPK model incorporated 11 tissue compartments, cerebrospinal fluid substructures, tissue substructures, endosomal trafficking, non\u2010specific binding in kidney and liver, and ASGPR\u2010mediated internalization for GalNAc\u2010siRNAs. Parameters for endocytosis, exocytosis, and degradation were estimated, and estimated values were compared with pre\u2010specified allometric exponents to assess physiological plausibility (i.e., as a consistency check rather than independent inference of scaling laws). The model captured plasma, liver, kidney, and CNS profiles across species, reproducing rapid systemic clearance with prolonged tissue half\u2010lives. Estimated parameter values for endocytosis, exocytosis, and non\u2010specific kidney binding were consistent with pre\u2010specified allometric exponents (\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009\u22120.25 and \u22120.2, respectively), supporting the physiological plausibility of the estimates. Sensitivity analyses identified endocytosis and rate of degradation as dominant determinants of systemic and tissue disposition. This work establishes a translational PBPK platform for unconjugated ASOs and GalNAc\u2010conjugated siRNAs, enabling quantitative interspecies extrapolation within the domain of the compounds, routes, and species studied. The framework provides a mechanistic basis to support dose selection, safety assessment, and clinical translation for these subclasses; extrapolation to other oligonucleotide subclasses (e.g., GalNAc\u2010ASOs, unconjugated siRNAs, LNP\u2010formulated oligonucleotides) will require additional datasets and dedicated validation.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70524","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:58:40Z","timestamp":1792130320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toward a Platform\n                    <scp>PBPK<\/scp>\n                    Model to Characterize the Plasma and Tissue Disposition of Unconjugated Antisense Oligonucleotides and\n                    <scp>GalNAc<\/scp>\n                    \u2010Conjugated Small Interfering\n                    <scp>RNAs<\/scp>\n                    in Preclinical Species and Human"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8880-8718","authenticated-orcid":false,"given":"Devam A.","family":"Desai","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-0343","authenticated-orcid":false,"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","DOI":"10.3390\/jcm9062004","article-title":"Antisense oligonucleotides: an emerging area in drug discovery and development","volume":"9","author":"Dhuri K.","year":"2020","journal-title":"J. Clin. Med."},{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1038\/s43856-023-00419-1","article-title":"Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders","volume":"4","author":"Lauffer M.C.","year":"2024","journal-title":"Commun. Med."},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.59566\/IJBS.2017.13048","article-title":"Molecular mechanisms and biological functions of siRNA","volume":"13","author":"Dana H.","year":"2017","journal-title":"Int. J. Biomed. Sci."},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1304342","article-title":"Antisense oligonucleotides: a novel Frontier in pharmacological strategy","volume":"14","author":"Collotta D.","year":"2023","journal-title":"Front. Pharmacol."},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2024.1393646","article-title":"Principle, application and challenges of development siRNA\u2010based therapeutics against bacterial and viral infections: a comprehensive review","volume":"15","author":"Motamedi H.","year":"2024","journal-title":"Front. Microbiol."},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms26083456","article-title":"Recent update on siRNA therapeutics","volume":"26","author":"Ebenezer O.","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.1177\/1756285618754459","article-title":"Nusinersen for spinal muscular atrophy","volume":"11","author":"Wurster C.D.","year":"2018","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"e_1_2_10_8_1","volume-title":"StatPearls [Internet]","author":"Joubran E.N.H.","year":"2025"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.2147\/DDDT.S281631","article-title":"Spotlight on Givosiran as a treatment option for adults with acute hepatic porphyria: design, development, and place in therapy","volume":"16","author":"Majeed C.N.","year":"2022","journal-title":"Drug Des. Devel. Ther."},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1260921","article-title":"Inclisiran: a new generation of lipid\u2010lowering siRNA therapeutic","volume":"14","author":"Zhang Y.","year":"2023","journal-title":"Front. Pharmacol."},{"key":"e_1_2_10_11_1","unstructured":"FDA.Approved cellular and gene therapy products<https:\/\/www.fda.gov\/vaccines\u2010blood\u2010biologics\/cellular\u2010gene\u2010therapy\u2010products\/approved\u2010cellular\u2010and\u2010gene\u2010therapy\u2010products> (2025)."},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2147\/IJNRD.S293682","article-title":"Lumasiran in the management of patients with primary hyperoxaluria type 1: from bench to bedside","volume":"15","author":"D'Ambrosio V.","year":"2022","journal-title":"Int. J. Nephrol. Renovasc. Dis."},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1124\/jpet.121.000805","article-title":"Minimal physiologically based pharmacokinetic\u2010pharmacodynamic (mPBPK\u2010PD) model of N\u2010Acetylgalactosamine\u2010conjugated small interfering RNA disposition and gene silencing in preclinical species and humans","volume":"379","author":"Ayyar V.S.","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.xphs.2023.10.026","article-title":"Mechanistic pharmacokinetics and pharmacodynamics of GalNAc\u2010siRNA: translational model involving competitive receptor\u2010mediated disposition and RISC\u2010dependent gene silencing applied to Givosiran","volume":"113","author":"Ayyar V.S.","year":"2024","journal-title":"J. Pharm. Sci."},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1007\/s11095-022-03333-8","article-title":"Pharmacokinetic and pharmacodynamic modeling of siRNA therapeutics \u2013 a minireview","volume":"39","author":"Jeon J.Y.","year":"2022","journal-title":"Pharm. Res."},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1124\/dmd.122.001107","article-title":"Clinical pharmacology of RNA interference\u2010based therapeutics: a summary based on Food and Drug Administration\u2010approved small interfering RNAs","volume":"51","author":"Jing X.","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1039\/D4MD00652F","article-title":"Hepatocyte targeting via the asialoglycoprotein receptor","volume":"16","author":"Ram\u00edrez\u2010Cort\u00e9s F.","year":"2025","journal-title":"RSC Med. Chem."},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2022.1090237","article-title":"The therapeutic prospects of N\u2010acetylgalactosamine\u2010siRNA conjugates","volume":"13","author":"Zhang L.","year":"2022","journal-title":"Front. Pharmacol."},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2023.1130925","article-title":"A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides","volume":"14","author":"Linninger A.A.","year":"2023","journal-title":"Front. Physiol."},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s10928-021-09761-0","article-title":"A physiologically\u2010based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration","volume":"48","author":"Monine M.","year":"2021","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2021.114468","article-title":"Physiologically based pharmacokinetic (PBPK) modeling of RNAi therapeutics: opportunities and challenges","volume":"189","author":"Fairman K.","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","DOI":"10.3389\/fsysb.2023.1180948","article-title":"Application of machine learning in combination with mechanistic modeling to predict plasma exposure of small molecules","volume":"3","author":"Mavroudis P.D.","year":"2023","journal-title":"Front. Syst. Biol."},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","DOI":"10.1124\/dmd.123.000960","article-title":"Physiologically based pharmacokinetic modeling of small molecules: how much progress have we made?","volume":"53","author":"Isoherranen N.","year":"2025","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cpt.3289","article-title":"Dose optimization informed by PBPK modeling: state\u2010of\u2010the art and future","volume":"116","author":"Rowland Yeo K.","year":"2024","journal-title":"Clin. Pharmacol. Ther."},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1016\/j.xphs.2017.03.038","article-title":"Physiologically based pharmacokinetic modeling of therapeutic proteins","volume":"106","author":"Wong H.","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10928-011-9232-2","article-title":"Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human","volume":"39","author":"Shah D.K.","year":"2012","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/psp4.12323","article-title":"A semi\u2010mechanistic population pharmacokinetic model of Nusinersen: an antisense oligonucleotide for the treatment of spinal muscular atrophy","volume":"7","author":"Biliouris K.","year":"2018","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.omtn.2024.102133","article-title":"Tissue pharmacokinetics of antisense oligonucleotides","volume":"35","author":"B\u00e4ckstr\u00f6m E.","year":"2024","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.129240","article-title":"Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging","volume":"4","author":"Mazur C.","year":"2019","journal-title":"JCI Insight"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.omtn.2022.07.027","article-title":"Identification and characterization of a MAPT\u2010targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies","volume":"29","author":"Easton A.","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1002\/psp4.13001","article-title":"Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma","volume":"12","author":"Yamamoto Y.","year":"2023","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/s41591-023-02326-3","article-title":"Tau\u2010targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo\u2010controlled trial","volume":"29","author":"Mummery C.J.","year":"2023","journal-title":"Nat. Med."},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"10969","DOI":"10.1093\/nar\/gkx818","article-title":"Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc\u2010siRNA conjugates","volume":"45","author":"Nair J.K.","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/nm.3847","article-title":"An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia","volume":"21","author":"Sehgal A.","year":"2015","journal-title":"Nat. Med."},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1124\/dmd.121.000381","article-title":"Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion of Givosiran, the first approved N\u2010Acetylgalactosamine\u2010conjugated RNA interference therapeutic","volume":"49","author":"Li J.","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_10_36_1","unstructured":"Lee J. Goel V.&Agarwal S.Pharmacokinetic\/pharmacodynamic analysis of givosiran in rats.ACoP10(2019)."},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s40262-022-01197-0","article-title":"Population pharmacokinetic analysis of the RNAi therapeutic Givosiran in patients with acute hepatic porphyria","volume":"62","author":"Melch M.","year":"2023","journal-title":"Clin. Pharmacokinet."},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1111\/jth.15270","article-title":"Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran\u2010results of the phase 1 inhibitor cohort","volume":"19","author":"Pasi K.J.","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"e_1_2_10_39_1","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1616569","article-title":"Targeting of antithrombin in hemophilia a or B with RNAi therapy","volume":"377","author":"Pasi K.J.","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_10_40_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2024.1454785","article-title":"A quantitative systems pharmacology (QSP) platform for preclinical to clinical translation of in\u2010vivo CRISPR\u2010Cas therapy","volume":"15","author":"Desai D.A.","year":"2024","journal-title":"Front. Pharmacol."},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1002916","article-title":"Spartan: a comprehensive tool for understanding uncertainty in simulations of biological systems","volume":"9","author":"Alden K.","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jtbi.2008.04.011","article-title":"A methodology for performing global uncertainty and sensitivity analysis in systems biology","volume":"254","author":"Marino S.","year":"2008","journal-title":"J. Theor. Biol."},{"key":"e_1_2_10_43_1","unstructured":"MATLAB.Simbiology \u2013 MATLAB 2022b ed(2022)."},{"key":"e_1_2_10_44_1","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting huntingtin expression in patients with Huntington's disease","volume":"380","author":"Tabrizi S.J.","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_10_45_1","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s10928-013-9332-2","article-title":"Second\u2010generation minimal physiologically\u2010based pharmacokinetic model for monoclonal antibodies","volume":"40","author":"Cao Y.","year":"2013","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"e_1_2_10_46_1","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/cpt.3316","article-title":"Beyond MABEL: an integrative approach to first in human dose selection of immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno\u2010Safety Technical Committee (ITC)","volume":"116","author":"Matsumoto M.","year":"2024","journal-title":"Clin. Pharmacol. Ther."},{"key":"e_1_2_10_47_1","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1177\/0192623320964391","article-title":"Urinary kidney biomarker panel detects preclinical antisense oligonucleotide\u2010induced tubular toxicity","volume":"48","author":"Sandelius \u00c5.","year":"2020","journal-title":"Toxicol. Pathol."},{"key":"e_1_2_10_48_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejps.2024.106838","article-title":"Application of physiologically based pharmacokinetic modeling of novel drugs approved by the U.S. Food and Drug Administration","volume":"200","author":"Sun Z.","year":"2024","journal-title":"Eur. J. Pharm. Sci."},{"key":"e_1_2_10_49_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/BF02353860","article-title":"Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125","volume":"22","author":"Kawai R.","year":"1994","journal-title":"J. Pharmacokinet. Biopharm."},{"key":"e_1_2_10_50_1","doi-asserted-by":"crossref","first-page":"6870","DOI":"10.1021\/acs.jmedchem.4c02528","article-title":"Metabolic stability and targeted delivery of oligonucleotides: advancing RNA therapeutics beyond the liver","volume":"68","author":"Anand P.","year":"2025","journal-title":"J. Med. Chem."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70524","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70524","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70524","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:58:47Z","timestamp":1792130327000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70524"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,15]]},"references-count":50,"alternative-id":["10.1002\/cpt.70524"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70524","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,15]]},"assertion":[{"value":"2026-02-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70524"}}