Model-Informed Precision Dosing Strategy for Sitagliptin and Duloxetine in Hepatic Cirrhosis: An Interventional Pilot Study

Model-Informed Precision Dosing Strategy for Sitagliptin and Duloxetine in Hepatic Cirrhosis: An Interventional Pilot Study | 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 Model-Informed Precision Dosing Strategy for Sitagliptin and Duloxetine in Hepatic Cirrhosis: An Interventional Pilot Study Aya Fouda, Noha M EL-Khodary, Ahmed A. Amin, Mohammed Hussien Ahmed Hussien, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9517990/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Purpose Liver cirrhosis can change antidiabetic and analgesic drug pharmacokinetics, mandating the need for dose modifications. Physiologically based pharmacokinetic PBPK modeling helps expect these pharmacokinetic alterations in cirrhotic patients and estimate dosage across various degrees of cirrhosis severities with subsequent evaluation of the recommended doses. Methods PBPK models were first validated in healthy participants and then adapted to incorporate cirrhosis‑related pathophysiological changes. Pharmacokinetic parameters such as area under the plasma concentration-time curve (AUC) and plasma maximum concentration (C max ) were predicted and compared with observed data. Dose adjustments were calculated to achieve unbound drug exposures comparable to those seen in healthy volunteers, and recommendations were made across Child–Pugh (CP) classes A, B, and C. Clinical evaluation was performed to assess the effectiveness and safety of PBPK‑guided dosing. Results Predicted AUC and C max values showed good agreement with observed data (within 2‑fold). The models were also used to predict unbound plasma AUC across various disease stages and to evaluate change in the dosing for untested cirrhotic populations. The latter results have been compared with the healthy population. The model-informed dose adjustment reduced duloxetine to 48.8%, 24.3%, and 11.6% and sitagliptin to 83.3%,71.4%, and 62.5% of their standard doses across CP classes A, B, and C, respectively. Clinical evaluation confirmed that PBPK‑guided dosing improved glycemic control and pain reduction while maintaining safety across cirrhosis severities. Conclusion Duloxetine kinetics are significantly affected by hepatic impairment, whereas sitagliptin shows modest pharmacokinetic changes. Integrating PBPK modeling with clinical evaluation provides reliable, evidence‑based guidance for dose optimization of these drugs in cirrhotic patients. Clinical Trial Registration ClinicalTrials.gov (Identifier: NCT07439536), registered retrospectively on 17 February 2026. PBPK Sitagliptin Duloxetine Diabetes Peripheral neuropathy Cirrhosis Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryinformationforsitagliptinandduloxetineEJCPdocx.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 30 Apr, 2026 Reviewers invited by journal 28 Apr, 2026 Editor assigned by journal 28 Apr, 2026 Submission checks completed at journal 28 Apr, 2026 First submitted to journal 24 Apr, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9517990","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":633060686,"identity":"dbadaa0b-53f3-4861-b182-7e524f73f337","order_by":0,"name":"Aya Fouda","email":"","orcid":"","institution":"Kafrelsheikh University","correspondingAuthor":false,"prefix":"","firstName":"Aya","middleName":"","lastName":"Fouda","suffix":""},{"id":633060687,"identity":"3e72eb1d-fe85-4240-9ee0-d88b579ae158","order_by":1,"name":"Noha M EL-Khodary","email":"","orcid":"","institution":"Kafrelsheikh University","correspondingAuthor":false,"prefix":"","firstName":"Noha","middleName":"M","lastName":"EL-Khodary","suffix":""},{"id":633060688,"identity":"8e4f507d-e32b-4ea5-82c3-5d16e6ce9b1a","order_by":2,"name":"Ahmed A. 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Physiologically based pharmacokinetic PBPK modeling helps expect these pharmacokinetic alterations in cirrhotic patients and estimate dosage across various degrees of cirrhosis severities with subsequent evaluation of the recommended doses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u0026nbsp;PBPK models were first validated in healthy participants and then adapted to incorporate cirrhosis‑related pathophysiological changes. Pharmacokinetic parameters such as\u0026nbsp;area\u0026nbsp;under the plasma concentration-time curve (AUC) and plasma maximum concentration (C\u003csub\u003emax\u003c/sub\u003e) were\u0026nbsp;predicted and compared with observed data. Dose adjustments were calculated to achieve unbound drug exposures\u0026nbsp;comparable to those seen in healthy volunteers,\u0026nbsp;and recommendations were made across Child–Pugh (CP) classes A, B, and C. Clinical evaluation was performed to assess the effectiveness and safety of PBPK‑guided dosing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u0026nbsp;Predicted AUC and C\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;values showed good agreement with observed data (within 2‑fold).\u0026nbsp;The models were also used to predict unbound plasma AUC across various disease stages and to evaluate change in the dosing for untested cirrhotic populations. The latter results have been compared with the healthy population. The model-informed dose adjustment reduced duloxetine to 48.8%, 24.3%, and 11.6% and sitagliptin to 83.3%,71.4%, and 62.5% of their standard doses across CP classes A, B, and C, respectively.\u0026nbsp;Clinical evaluation confirmed that PBPK‑guided dosing improved glycemic control and pain reduction while maintaining safety across cirrhosis severities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u0026nbsp;Duloxetine kinetics are significantly affected by hepatic impairment, whereas sitagliptin shows modest pharmacokinetic changes. Integrating PBPK modeling with clinical evaluation provides reliable, evidence‑based guidance for dose optimization of these drugs in cirrhotic patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinicalTrials.gov\u0026nbsp;(Identifier: NCT07439536), registered retrospectively on 17 February 2026.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Model-Informed Precision Dosing Strategy for Sitagliptin and Duloxetine in Hepatic Cirrhosis: An Interventional Pilot Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-06 22:15:31","doi":"10.21203/rs.3.rs-9517990/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"54170608850326325119656912349833520051","date":"2026-04-30T14:19:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-28T13:32:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-28T06:20:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-28T06:20:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Pharmacology","date":"2026-04-24T13:46:18+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":"e0ce514f-61b8-499f-afe2-9c1f8cd346d5","owner":[],"postedDate":"May 6th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"54170608850326325119656912349833520051","date":"2026-04-30T14:19:13+00:00","index":13,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T22:15:31+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-06 22:15:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9517990","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9517990","identity":"rs-9517990","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}