Population Pharmacokinetics of Rivaroxaban After Transjugular Intrahepatic Portosystemic Shunt

Population Pharmacokinetics of Rivaroxaban After Transjugular Intrahepatic Portosystemic Shunt | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Population Pharmacokinetics of Rivaroxaban After Transjugular Intrahepatic Portosystemic Shunt Min Jia, Yiming Chai, Yuan Gao, Changyou Jing, Kunlei Zhu, Tong Zhu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7830914/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Mar, 2026 Read the published version in European Journal of Clinical Pharmacology → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein hypercoagulability to avoid stent thrombosis. As TIPS shunts portal blood directly into the systemic circulation and may substantially affect the first-pass extraction/distribution of direct oral anticoagulants, no population prospective pharmacokinetic studies have been published in patients undergoing TIPS placement so far. The goal of this study was to establish a PopPK model for rivaroxaban in post-TIPS patients, investigate clinical covariate effects on PK, and provide an optimized dosing regimen. Methods In this single-centre prospective study, 39 adult patients underwent TIPS and received rivaroxaban 5 or 10 mg once daily thereafter. Population PK analysis was conducted in NONMEM with 131 plasma concentrations available from 38 evaluable patients (median age: 56 years; median body weight: 63.8 kg). Parameterized model was then applied to simulate steady-state exposure of 5, 7.5, 10, and 15mg once daily regimen. Results The final PopPK model was based on a one-compartment with sequential zero-order followed by first-order absorption kinetics, and included the effects of an absorption lag time and linear elimination. The apparent clearance and volume of distribution were 7.48 L/h and 4.75 L, respectively. Based on patient-specific simulations of 38 subjects, at the 5 mg/day dose, an exposure within predefined limits was potentially preserved in 96.7% of the cases vs. 62.5% for the 10 mg/day (thresholds: AUC ss,24 ≤ 1.77 mg·h/L and C max,ss ≤ 140 µg/L). This trend was confirmed by Monte-Carlo simulations in 1,000 virtual patients and suggests TDM when the higher dosage is given. Conclusions This PopPK model provides an initial characterisation of rivaroxaban disposition in post-TIPS patients and reveals a markedly reduced apparent V/F relative to non-TIPS populations. The 5 mg once-daily regimen is generally safe, while the 10 mg dose may be considered with therapeutic drug monitoring to account for substantial inter-individual pharmacokinetic variability in post-TIPS patients. Trial Registration Chinese Clinical Trial Registry, ChiCTR (ChiCTR2300073784); registered 20 July 2023. Rivaroxaban Population pharmacokinetics (PopPK) Transjugular intrahepatic portosystemic shunt (TIPS) Model-informed dosing Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Mar, 2026 Read the published version in European Journal of Clinical Pharmacology → Version 1 posted Editorial decision: Revision requested 22 Dec, 2025 Reviews received at journal 21 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviews received at journal 21 Nov, 2025 Reviewers agreed at journal 03 Nov, 2025 Reviewers invited by journal 21 Oct, 2025 Editor assigned by journal 20 Oct, 2025 Submission checks completed at journal 20 Oct, 2025 First submitted to journal 10 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7830914","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":534260870,"identity":"bdf7d5c0-ee0b-43e9-a51a-244e50c3c73b","order_by":0,"name":"Min Jia","email":"","orcid":"","institution":"Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Jia","suffix":""},{"id":534260871,"identity":"8755389a-7e61-4a30-a278-c4883580a0e9","order_by":1,"name":"Yiming Chai","email":"","orcid":"","institution":"Zhongchuang Huiming 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Shunt","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Rivaroxaban, Population pharmacokinetics (PopPK), Transjugular intrahepatic portosystemic shunt (TIPS), Model-informed dosing","lastPublishedDoi":"10.21203/rs.3.rs-7830914/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7830914/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003e Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein hypercoagulability to avoid stent thrombosis. As TIPS shunts portal blood directly into the systemic circulation and may substantially affect the first-pass extraction/distribution of direct oral anticoagulants, no population prospective pharmacokinetic studies have been published in patients undergoing TIPS placement so far. The goal of this study was to establish a PopPK model for rivaroxaban in post-TIPS patients, investigate clinical covariate effects on PK, and provide an optimized dosing regimen.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eIn this single-centre prospective study, 39 adult patients underwent TIPS and received rivaroxaban 5 or 10 mg once daily thereafter. Population PK analysis was conducted in NONMEM with 131 plasma concentrations available from 38 evaluable patients (median age: 56 years; median body weight: 63.8 kg). Parameterized model was then applied to simulate steady-state exposure of 5, 7.5, 10, and 15mg once daily regimen.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe final PopPK model was based on a one-compartment with sequential zero-order followed by first-order absorption kinetics, and included the effects of an absorption lag time and linear elimination. The apparent clearance and volume of distribution were 7.48 L/h and 4.75 L, respectively. Based on patient-specific simulations of 38 subjects, at the 5 mg/day dose, an exposure within predefined limits was potentially preserved in 96.7% of the cases vs. 62.5% for the 10 mg/day (thresholds: AUC\u003csub\u003ess,24\u003c/sub\u003e \u0026le; 1.77 mg\u0026middot;h/L and C\u003csub\u003emax,ss\u003c/sub\u003e \u0026le; 140 \u0026micro;g/L). This trend was confirmed by Monte-Carlo simulations in 1,000 virtual patients and suggests TDM when the higher dosage is given.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis PopPK model provides an initial characterisation of rivaroxaban disposition in post-TIPS patients and reveals a markedly reduced apparent V/F relative to non-TIPS populations. The 5 mg once-daily regimen is generally safe, while the 10 mg dose may be considered with therapeutic drug monitoring to account for substantial inter-individual pharmacokinetic variability in post-TIPS patients.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e\u003cp\u003eChinese Clinical Trial Registry, ChiCTR (ChiCTR2300073784); registered 20 July 2023.\u003c/p\u003e","manuscriptTitle":"Population Pharmacokinetics of Rivaroxaban After Transjugular Intrahepatic Portosystemic Shunt","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-03 07:00:29","doi":"10.21203/rs.3.rs-7830914/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T11:23:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-22T04:29:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"329229842519225837904298519976637698215","date":"2025-12-01T07:23:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T13:57:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336812098023771288735125428456837168194","date":"2025-11-03T18:23:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-21T17:03:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-20T12:50:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-20T12:48:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Pharmacology","date":"2025-10-11T02:10:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c65ba784-ee3e-460f-aa47-6ea88d995d52","owner":[],"postedDate":"November 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:22:14+00:00","versionOfRecord":{"articleIdentity":"rs-7830914","link":"https://doi.org/10.1007/s00228-026-04034-6","journal":{"identity":"european-journal-of-clinical-pharmacology","isVorOnly":false,"title":"European Journal of Clinical Pharmacology"},"publishedOn":"2026-03-24 16:10:08","publishedOnDateReadable":"March 24th, 2026"},"versionCreatedAt":"2025-11-03 07:00:29","video":"","vorDoi":"10.1007/s00228-026-04034-6","vorDoiUrl":"https://doi.org/10.1007/s00228-026-04034-6","workflowStages":[]},"version":"v1","identity":"rs-7830914","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7830914","identity":"rs-7830914","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}