Population pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5.

Population pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5. | 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 pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5. Shingirai Melidith Chiwambutsa, Ali Mahomed Ali, Herbert Cubasch, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5381954/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Wide inter-individual variability is seen in the clinical outcomes of tamoxifen treatment, which may be attributable to cytochrome P450 genetic polymorphisms. To investigate this, we analysed data from an open-label three parallel arm trial with 36 healthy volunteers of African ancestry to whom a dose of 20 mg of tamoxifen had been administered and drug concentrations of tamoxifen and its three metabolites measured over 34 time points after administration. Methods The data was best described by a pharmacokinetic model, which focused on tamoxifen and its active metabolite endoxifen only. The model was described by a two-compartment model for the parent linked to a one-compartment model for the metabolite. Results Data exploration and estimated pharmacokinetic parameters for both compounds indicated wide variability between participants. The findings demonstrated high inter individual variability (99.3%) in the formation of endoxifen with no evidence to suggest that the CYP2D6 gene could explain this variation. Model diagnostic plots such as goodness of fit plots and visual predictive checks showed a good predictive performance of the model. Conclusion Age, BMI, CYP2D6 , CYP3A4 , CYP3A5 , CYP2B6 , CYP2C9 and CYP2C19 genotypes had no significant impact in explaining the variability in pharmacokinetic parameters for tamoxifen and endoxifen. Tamoxifen pharmacokinetics pharmacogenetics inter-individual variability biotransformation CYP2D6 Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-5381954","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":374466679,"identity":"d8c6e7c7-e1c9-4c7d-9948-e1d1689e50d6","order_by":0,"name":"Shingirai Melidith 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volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tamoxifen, pharmacokinetics, pharmacogenetics, inter-individual variability, biotransformation, CYP2D6","lastPublishedDoi":"10.21203/rs.3.rs-5381954/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5381954/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eWide inter-individual variability is seen in the clinical outcomes of tamoxifen treatment, which may be attributable to cytochrome P450 genetic polymorphisms. To investigate this, we analysed data from an open-label three parallel arm trial with 36 healthy volunteers of African ancestry to whom a dose of 20 mg of tamoxifen had been administered and drug concentrations of tamoxifen and its three metabolites measured over 34 time points after administration.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe data was best described by a pharmacokinetic model, which focused on tamoxifen and its active metabolite endoxifen only. The model was described by a two-compartment model for the parent linked to a one-compartment model for the metabolite.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eData exploration and estimated pharmacokinetic parameters for both compounds indicated wide variability between participants. The findings demonstrated high inter individual variability (99.3%) in the formation of endoxifen with no evidence to suggest that the \u003cem\u003eCYP2D6\u003c/em\u003e gene could explain this variation. 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