{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:17:51Z","timestamp":1792642671321,"version":"4.5.0"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005205","name":"Janssen Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005205","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:p>JNJ\u201073763989 is a combination product consisting of two N\u2010acetylgalactosamine\u2010conjugated short\u2010interfering RNA triggers (JNJ\u201073763976 and JNJ\u201073763924) that are in development as a potential treatment for chronic hepatitis B virus infection. A population pharmacokinetic model for JNJ\u201073763989 was developed based on pooled data from seven clinical studies to characterize the plasma pharmacokinetics of the short\u2010interfering RNAs following subcutaneous administration. Additionally, simulations of liver (target organ) exposure using the final population pharmacokinetic model in conjunction with preclinical information were performed. Disposition of JNJ\u201073763976 and JNJ\u201073763924 was governed by a linear two\u2010compartment model describing the peripheral distribution of both short\u2010interfering RNAs and a saturable component describing liver uptake via the asialoglycoprotein receptor. While the estimated first\u2010order absorption rate constant was similar for both short\u2010interfering RNAs, the corresponding absorption half\u2010life values were 20\u2010 to 40\u2010fold longer than the estimated plasma elimination half\u2010life for both short\u2010interfering RNAs, indicating absorption rate\u2010limited or \u201cflip\u2010flop\u201d kinetics. Plasma\u2010to\u2010liver transport of each short\u2010interfering RNA was modeled by a saturable, receptor\u2010mediated competitive process, and the affinity for the asialoglycoprotein receptor was 2.5\u2010fold higher for JNJ\u201073763924 relative to JNJ\u201073763976. Predicted liver concentrations of both short\u2010interfering RNA triggers approached steady state after 12\u2009months of JNJ\u201073763989 treatment. The 2:1 dosing ratio of JNJ\u201073763976 to JNJ\u201073763924 was predicted to maintain an ~2:1 liver concentration ratio, irrespective of the identified plasma disposition differences between the triggers. Body weight, creatinine clearance, presence of chronic hepatitis B, and hepatic impairment were associated with plasma pharmacokinetic parameters and were included in the final population pharmacokinetic model.<\/jats:p>","DOI":"10.1002\/cpt.3690","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T23:15:11Z","timestamp":1747350911000},"page":"1451-1462","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Population Pharmacokinetics of\n                    <scp>siRNA JNJ<\/scp>\n                    \u201073763989 in Healthy Participants and\u00a0Patients With Chronic Hepatitis B"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6370-8419","authenticated-orcid":false,"given":"Tetsuro","family":"Ogawa","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0526-5318","authenticated-orcid":false,"given":"Nele","family":"Goeyvaerts","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-2572","authenticated-orcid":false,"given":"Thomas N.","family":"Kakuda","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3284-2977","authenticated-orcid":false,"given":"Joris J.","family":"Vandenbossche","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"P\u00e9rez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5908-5200","authenticated-orcid":false,"given":"Oliver","family":"Ackaert","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Njumbe Ediage","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6993-8206","authenticated-orcid":false,"given":"Michael","family":"Biermer","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Lenz","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University Medical Center Groningen, University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-9926","authenticated-orcid":false,"given":"Huybrecht","family":"T\u2019jollyn","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010213"},{"key":"e_1_2_10_2_1","unstructured":"WHO.Hepatits B<https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/hepatitis\u2010b>. Accessed December 13 2023."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2004.10.026"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.05.008"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.85"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.122.001229"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa670"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx818"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/13596535221093856"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2214"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1197"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.07.010"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1974"},{"key":"e_1_2_10_14_1","unstructured":"Kakuda T.N.Pharmacokinetics of the small interfering RNA (siRNA) JNJ\u201073763989 and capsid assembly modulator (CAM) JNJ\u201056136379 in patients with chronic hepatitis B (CHB): REEF\u20101 and REEF\u20102 pharmacokinetic substudy. Presented at the International Workshop on Clinical Pharmacology of HIV Hepatitis and Other Antiviral Drugs 2022."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio.15.234"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-016-9502-0"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-012-9267-z"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-328041"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01061469"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-015-9417-1"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-022-01197-0"},{"key":"e_1_2_10_22_1","first-page":"1798","article-title":"Asialoglycoprotein receptor and hepatic blood flow using technetium\u201099m\u2010DTPA\u2010galactosyl human serum albumin","volume":"38","author":"Miki K.","year":"1997","journal-title":"J. Nucl. 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