Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer

Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer | 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 and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer Aburough Abegesah, Do-Youn Oh, KyoungSoo Lim, Chunling Fan, Cecil Chen, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4576395/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2025 Read the published version in Cancer Chemotherapy and Pharmacology → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: Durvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1. Methods: The PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response (ER) analysis related to efficacy and safety. Results: Consistent with previous analyses, the durvalumab pharmacokinetics in BTC followed a 2-compartment model with time-dependent clearance. The final population parameters were: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease up to 39% over the time course of treatment. There were 111 patients (3.53%) with treatment-emergent ADA positive in the pooled group of 6 studies, and the exposure was comparable for ADA positive and negative patients. Covariates had minimal clinical impact on PopPK parameters. No significant associations were found between exposure and overall survival (OS), progression-free survival (PFS), using Cox proportional analysis (CPH). Logistic regression analysis indicated no significant relationship between the exposure and relevant adverse events measures of Grade 3 and higher treatment-related AE, Grade 3 and higher treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation. Conclusions: No dose adjustment for durvalumab is needed based on PopPK and ERES analyses. The analysis supports the TOPAZ-1 regimen for patients with advanced BTC. population pharmacokinetics exposure-response analysis durvalumab advanced biliary tract cancer Full Text Additional Declarations Competing interest reported. AA, KL, CF, CC, JW, IX, MZ, SR, MG, and DZ are current employees of and shareholders in AstraZeneca. CK and AP are former employees of AstraZeneca. DYO is a consultant and on the advisory board for: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, Abbvie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. DYO has also received research grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok. Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2025 Read the published version in Cancer Chemotherapy and Pharmacology → Version 1 posted Editorial decision: Revision requested 07 Aug, 2024 Reviews received at journal 08 Jul, 2024 Reviewers agreed at journal 17 Jun, 2024 Reviewers invited by journal 16 Jun, 2024 Editor assigned by journal 13 Jun, 2024 Submission checks completed at journal 13 Jun, 2024 First submitted to journal 13 Jun, 2024 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. 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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-4576395","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":337360133,"identity":"b925cec2-89f1-4492-8515-7fefd4f38908","order_by":0,"name":"Aburough 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Quantitative Pharmacology, BioPharmaceuticals R\u0026D, AstraZeneca, Waltham","correspondingAuthor":false,"prefix":"","firstName":"Diansong","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2024-06-13 13:06:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4576395/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4576395/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00280-024-04743-8","type":"published","date":"2025-01-17T15:57:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":74285690,"identity":"a04b1e94-d41d-4c8f-a898-82119c87c63d","added_by":"auto","created_at":"2025-01-20 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AA, KL, CF, CC, JW, IX, MZ, SR, MG, and DZ are current employees of and shareholders in AstraZeneca.\nCK and AP are former employees of AstraZeneca. \nDYO is a consultant and on the advisory board for: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, Abbvie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. DYO has also received research grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok.","formattedTitle":"Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer","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":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"population pharmacokinetics, exposure-response analysis, durvalumab, advanced biliary tract cancer","lastPublishedDoi":"10.21203/rs.3.rs-4576395/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4576395/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eDurvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response (ER) analysis related to efficacy and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eConsistent with previous analyses, the durvalumab pharmacokinetics in BTC followed a 2-compartment model with time-dependent clearance. The final population parameters were: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease up to 39% over the time course of treatment. There were 111 patients (3.53%) with treatment-emergent ADA positive in the pooled group of 6 studies, and the exposure was comparable for ADA positive and negative patients. Covariates had minimal clinical impact on PopPK parameters. No significant associations were found between exposure and overall survival (OS), progression-free survival (PFS), using Cox proportional analysis (CPH). Logistic regression analysis indicated no significant relationship between the exposure and relevant adverse events measures of Grade 3 and higher treatment-related AE, Grade 3 and higher treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e No dose adjustment for durvalumab is needed based on PopPK and ERES analyses. The analysis supports the TOPAZ-1 regimen for patients with advanced BTC.\u003c/p\u003e","manuscriptTitle":"Population Pharmacokinetics and Exposure-Response Analysis of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 10:21:19","doi":"10.21203/rs.3.rs-4576395/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-07T18:47:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-08T05:37:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"211323366320119106725143697605386401023","date":"2024-06-17T20:09:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-17T02:50:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-14T03:54:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-14T03:54:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Chemotherapy and Pharmacology","date":"2024-06-13T13:05:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4c357370-b66b-4fa8-9796-561e109c70bf","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:10:11+00:00","versionOfRecord":{"articleIdentity":"rs-4576395","link":"https://doi.org/10.1007/s00280-024-04743-8","journal":{"identity":"cancer-chemotherapy-and-pharmacology","isVorOnly":false,"title":"Cancer Chemotherapy and Pharmacology"},"publishedOn":"2025-01-17 15:57:47","publishedOnDateReadable":"January 17th, 2025"},"versionCreatedAt":"2024-08-26 10:21:19","video":"","vorDoi":"10.1007/s00280-024-04743-8","vorDoiUrl":"https://doi.org/10.1007/s00280-024-04743-8","workflowStages":[]},"version":"v1","identity":"rs-4576395","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4576395","identity":"rs-4576395","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}