{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:57:26Z","timestamp":1792173446731,"version":"4.4.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"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":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Hereditary angioedema (HAE) is a rare disorder linked to kallikrein\u2010kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic\/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic\/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744\u2010CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80\u2009mg every 4\u2009weeks (Q4W) and 80\u2009mg every 8\u2009weeks (Q8W), administered subcutaneously over 13\u201321\u2009weeks. Donidalorsen pharmacokinetics were well described by a linear 2\u2010compartment model with first\u2010order absorption. The population terminal elimination half\u2010life was 31.4\u2009days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic\/pharmacodynamic model well characterized the donidalorsen exposure\u2013prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic\/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every\u20102\u2010month dosing regimens support switching to more convenient regimens for patients.<\/jats:p>","DOI":"10.1002\/psp4.70206","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T05:33:20Z","timestamp":1770010400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Population Pharmacokinetic\/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-4680","authenticated-orcid":false,"given":"John K.","family":"Diep","sequence":"first","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Liu","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratap","family":"Singh","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Dorow","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-3723","authenticated-orcid":false,"given":"Danny M.","family":"Cohn","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bordone","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Newman","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Ionis  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.05.055"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.5604\/01.3001.0014.0619"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.waojou.2023.100792"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2023.01.023"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2020.02.018"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13223\u2010021\u201000537\u20102"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010024\u201003265\u2010z"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325\u2010022\u201002401\u20100"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.5152\/balkanmedj.2021.21094"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13223\u2010019\u20100376\u20108"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2020.08.046"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.15214"},{"key":"e_1_2_9_14_1","unstructured":"Takhzyro (Lanadelumab\u2010Flyo) \u201cFull Prescribing Information \u201d(2023) Takeda Pharmaceuticals https:\/\/www.shirecontent.com\/PI\/PDFs\/TAKHZYRO_USA_ENG.pdf."},{"key":"e_1_2_9_15_1","unstructured":"Orladeyo (Berotralstat) Capsules \u201cFull Prescribing Information \u201d(2024) BioCryst Pharmaceuticals Inc. https:\/\/www.biocryst.com\/wp\u2010content\/uploads\/ORLADEYO_USPI.pdf."},{"key":"e_1_2_9_16_1","unstructured":"\u201cCinyryze (C1 Esterase Inhibitor [Human]) for Intravenous Use \u201d(2023) Full Prescribing Information. 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E.Manning L.Bordone D. M.Cohn et\u00a0al. \u201cPhase 2 Open\u2010Label Extension of Donidalorsen in Patients With Hereditary Angioedema: A Week 196 Analysis \u201dPoster Presented at the American College of Allergy Asthma and Immunology Annual Meeting. 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