{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:20:09Z","timestamp":1787664009374,"version":"build-2736575974"},"reference-count":37,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Eplontersen is a GalNAc\u2010conjugated antisense oligonucleotide (ASO) approved for the treatment of hereditary transthyretin\u2010mediated amyloidosis with polyneuropathy (ATTRv\u2010PN). GalNAc conjugation enables targeted hepatic delivery and improved potency compared with unconjugated ASOs. The clinical pharmacology of eplontersen was characterized by using in vitro studies and data from three Phase 1 studies in healthy participants and one pivotal Phase 3 study in patients with ATTRv\u2010PN. Following subcutaneous administration, eplontersen was rapidly absorbed and exhibited a biphasic pharmacokinetic (PK) profile with a terminal half\u2010life of approximately 3 weeks, supporting once\u2010monthly dosing. Eplontersen is highly plasma protein\u2011bound, distributes predominantly within the plasma compartment before receptor\u2011mediated tissue uptake, and is eliminated mainly via nuclease\u2011mediated metabolism, with minimal renal excretion of intact drug. Across integrated population PK\/PKPD and exposure\u2013response analyses at 45 mg Q4W, eplontersen exhibits predictable PK, robust PD, exposure\u2010independent efficacy within the achieved range, and no exposure\u2010dependent safety signals. Albeit some covariates were identified as statistically significant for population PK and population PKPD models, they were not considered clinically meaningful when taking into account the overall variability in PK, their minimal impact on TTR reduction, and the therapeutic window for eplontersen. These findings support that 45 mg Q4W is appropriate for patients with ATTRv\u2010PN without the need for dose modification. In vitro and model\u2010based analyses indicate low potential for clinically relevant plasma protein binding displacement and CYP\u2010 or transporter\u2010mediated drug\u2013drug interactions, and demonstrate no clinically meaningful effects on the QT prolongation and a predominantly non\u2010neutralizing anti\u2010drug antibody profile without impact on efficacy or safety.<\/jats:p>","DOI":"10.1002\/jcph.70276","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T06:33:56Z","timestamp":1787553236000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Pharmacology of Eplontersen, the First Approved GalNAc\u2010Conjugated Antisense Oligonucleotide"],"prefix":"10.1002","volume":"66","author":[{"given":"Rosie Z.","family":"Yu","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Diep","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7081-0573","authenticated-orcid":false,"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Arfvidsson","sequence":"additional","affiliation":[{"name":"Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences R&amp;D  AstraZeneca, Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Quartino","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010716-104846"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku531"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7051-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2018.0753"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2018.1556156"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805689"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.18688"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1974"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.08.012"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2013.05.005"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13154"},{"key":"e_1_2_9_14_1","unstructured":"UeckertS DiepJ ParkinsonJ et\u00a0al.Population PKPD and exposure\u2010response analysis of eplontersen supports 45 mg SC Q4W without dose adjustment in hereditary transthyretin\u2010mediated polyneuropathy. Paper presented at: 34th Annual Meeting of the Population Approach Group in Europe (PAGE);2026;Dubrovnik Croatia."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15468"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-014-9599-2"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2020.0911"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2020.0867"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2016.31"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250902877680"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2013.737320"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2015.01.008"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2019.1621838"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00162-z"},{"key":"e_1_2_9_26_1","volume-title":"Clinical pharmacology considerations for the development of oligonucleotide therapeutics: guidance for industry.","author":"US Food and Drug Administration","year":"2024"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.2165\/0003088-200948010-00003"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2015.0588"},{"issue":"12","key":"e_1_2_9_29_1","first-page":"99","article-title":"Assessment of drug\u2010drug interaction potential for antisense oligonucleotide therapeutics","volume":"9","author":"Wang Y","year":"2021","journal-title":"EC Pharmacol Toxicol"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12397"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2021.0112"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/21593337251387423"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-015-1992-y"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2019.0837"},{"issue":"6","key":"e_1_2_9_35_1","first-page":"1284","article-title":"Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects","volume":"80","author":"Rabinovich\u2010Guilatt L","year":"2015","journal-title":"Br J Clin Pharmacol"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2017.0676"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.119.087395"},{"key":"e_1_2_9_38_1","unstructured":"GaoX YuRZ SinghP et\u00a0al.Bioequivalence study comparing vial and autoinjector for eplontersen olezarsen and donidalorsen in healthy adult participants. 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