Development of an Isavuconazole Physiologically-based Pharmacokinetic Model for Adult and Pediatric Populations

Development of an Isavuconazole Physiologically-based Pharmacokinetic Model for Adult and Pediatric Populations | 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 Development of an Isavuconazole Physiologically-based Pharmacokinetic Model for Adult and Pediatric Populations Mary P Choules, Amit Desai, Laura Lynn Kovanda, Yukio Otsuka, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9292849/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 Isavuconazonium sulfate is the water-soluble prodrug of the active triazole antifungal agent isavuconazole. Isavuconazonium sulfate is approved for use as iv formulation in adult and pediatric patients > 1 year in age and as oral formulation in adult and pediatric patients > 6 years old and weight > 16 kg for treatment of invasive aspergillosis and invasive mucormycosis. In the present analysis, an isavuconazole physiologically-based pharmacokinetic (PBPK) model was built and verified in adult and pediatric populations using the Simcyp® simulator. The verified pediatric model was then used to predict the magnitude of DDI risk in pediatric population vs the adult population. The simulations conducted were designed to match the observed clinical trials conducted in adults but with pediatric equivalent doses based on clinical guidelines. Based on the results of the analysis, isavuconazole DDI risk was similar between pediatric and adult populations. When the isavuconazole perpetrator DDI simulations were compared to adults, there was a trend of larger geometric mean (GM) AUC inf and C max ratios in patients 1 to < 3 years old. The GM AUC inf ratio in the 1 to < 3-year-old population ranged from 7 to 36% larger than predicted in the adult population. Based on the results of this analysis and literature reports, it is advisable to show greater caution when considering potential DDI in patients < 3-year-old. In addition, caution should be used in patients < 3 years-old when considering coadministration of isavuconazole with narrow therapeutic index medications such as digoxin and warfarin or medications with large variability in oral bioavailability such as midazolam. Physiological-based pharmacokinetics (PBPK) drug-drug interaction (DDI) Simcyp isavuconazole antifungal pediatric DDI Full Text Additional Declarations Competing interest reported. Mary P Choules, Yukio Otsuka, Amit Desai, Laura Lynn Kovanda, and Peter L Bonate are all employees of Astellas Pharma Inc. Yukio Otsuka is a stockholder of Astellas Pharma, Inc. R.B. has served as a consultant to Astellas Pharma Inc., F2G, Amplyx, Basilea, Elion Tx, Gilead Sciences, Merck Sharp & Dohme Corp., Mundipharma, Pfizer, Inc., and Pulmocide, and has received unrestricted research grants from Astellas Pharma Inc., Basilea, Elion, Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc. All contracts were through Radboudumc, and all payments were invoiced by Radboudumc. Supplementary Files SupplementalChoulesISAPBPKfinal.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 10 Apr, 2026 Editor assigned by journal 09 Apr, 2026 Submission checks completed at journal 03 Apr, 2026 First submitted to journal 01 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-9292849","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620667165,"identity":"1c2dc12e-d9f5-4ed0-98ff-e85c61a175cf","order_by":0,"name":"Mary P Choules","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIie3PMUvDQBTA8fd4ki6HWV8I5BsUDgJHQalfpUWISz+AQwiRg3TSuR/DyTnwIC5K1wpuQuZIQOIipoN0kIS6Odx/uePuftwdgMv1fysBJv3Q7OcTyo8kBIAbAAbCPxBSx5Dp+rlmSF8jLSTteZplPuHNewfzaDogzdOVYajqWIuXhKtKOLBoQwWXsSkHSJl4jLks70UZWnkla8E87J+6fBgi2/qH+G07+8r4QtB+dmNkd7gFQiyINWHBapTUNFtUEgfimeD2ToKNYHGm9MhftgnumlSi00f71nQfme+vrbx01/NoiPSd8OL3oh48vo+a0W2Xy+VyfQOB+Vo31Y7eGQAAAABJRU5ErkJggg==","orcid":"","institution":"Astellas Pharma Global, Inc","correspondingAuthor":true,"prefix":"","firstName":"Mary","middleName":"P","lastName":"Choules","suffix":""},{"id":620667166,"identity":"a309c41f-c482-4db0-b2c5-0b9f5b4f4231","order_by":1,"name":"Amit Desai","email":"","orcid":"","institution":"Astellas Pharma Global, Inc","correspondingAuthor":false,"prefix":"","firstName":"Amit","middleName":"","lastName":"Desai","suffix":""},{"id":620667167,"identity":"ae2e0537-6e1f-4b06-ab26-3f8b9302ec67","order_by":2,"name":"Laura Lynn Kovanda","email":"","orcid":"","institution":"Astellas Pharma Global, Inc","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"Lynn","lastName":"Kovanda","suffix":""},{"id":620667168,"identity":"5ff463d6-f10c-453f-ab13-18944af1ec94","order_by":3,"name":"Yukio Otsuka","email":"","orcid":"","institution":"Astellas Pharma, Inc","correspondingAuthor":false,"prefix":"","firstName":"Yukio","middleName":"","lastName":"Otsuka","suffix":""},{"id":620667170,"identity":"3cb8005c-4d38-4f86-b35f-c3bf78d5df6d","order_by":4,"name":"Roger J Brüggemann","email":"","orcid":"","institution":"Radboud University Nijmegen Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Roger","middleName":"J","lastName":"Brüggemann","suffix":""},{"id":620667172,"identity":"a5c54a11-1eef-461f-a4f9-e6a0f62323e6","order_by":5,"name":"Peter L Bonate","email":"","orcid":"","institution":"Astellas Pharma Global, Inc","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"L","lastName":"Bonate","suffix":""}],"badges":[],"createdAt":"2026-04-01 13:54:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9292849/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9292849/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107483081,"identity":"e8a227ae-4384-4070-9f99-1d8b07f3a021","added_by":"auto","created_at":"2026-04-22 02:26:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":464390,"visible":true,"origin":"","legend":"","description":"","filename":"ChoulesISAPBPKfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9292849/v1_covered_d5301c69-2084-4fc2-a49c-c72118a895d2.pdf"},{"id":107179707,"identity":"976ea07d-ee61-4dd5-b6c5-d02e09a1886b","added_by":"auto","created_at":"2026-04-17 16:49:16","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":719107,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalChoulesISAPBPKfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-9292849/v1/7e2d0f951ea697bacef075b8.docx"}],"financialInterests":"Competing interest reported. Mary P Choules, Yukio Otsuka, Amit Desai, Laura Lynn Kovanda, and Peter L Bonate are all employees of Astellas Pharma Inc. Yukio Otsuka is a stockholder of Astellas Pharma, Inc. R.B. has served as a consultant to Astellas Pharma Inc., F2G, Amplyx, Basilea, Elion Tx, Gilead Sciences, Merck Sharp \u0026 Dohme Corp., Mundipharma, Pfizer, Inc., and Pulmocide, and has received unrestricted research grants from Astellas Pharma Inc., Basilea, Elion, Gilead Sciences, Merck Sharp \u0026 Dohme Corp., and Pfizer, Inc. 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Isavuconazonium sulfate is approved for use as iv formulation in adult and pediatric patients\u0026thinsp;\u0026gt;\u0026thinsp;1 year in age and as oral formulation in adult and pediatric patients\u0026thinsp;\u0026gt;\u0026thinsp;6 years old and weight\u0026thinsp;\u0026gt;\u0026thinsp;16 kg for treatment of invasive aspergillosis and invasive mucormycosis. In the present analysis, an isavuconazole physiologically-based pharmacokinetic (PBPK) model was built and verified in adult and pediatric populations using the Simcyp\u0026reg; simulator. The verified pediatric model was then used to predict the magnitude of DDI risk in pediatric population vs the adult population. The simulations conducted were designed to match the observed clinical trials conducted in adults but with pediatric equivalent doses based on clinical guidelines. Based on the results of the analysis, isavuconazole DDI risk was similar between pediatric and adult populations. When the isavuconazole perpetrator DDI simulations were compared to adults, there was a trend of larger geometric mean (GM) AUC\u003csub\u003einf\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e ratios in patients 1 to \u0026lt;\u0026thinsp;3 years old. The GM AUC\u003csub\u003einf\u003c/sub\u003e ratio in the 1 to \u0026lt;\u0026thinsp;3-year-old population ranged from 7 to 36% larger than predicted in the adult population. Based on the results of this analysis and literature reports, it is advisable to show greater caution when considering potential DDI in patients\u0026thinsp;\u0026lt;\u0026thinsp;3-year-old. 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