A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated

A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated | 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 A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated Liam V Brown, Alberto Ippolito, Mark Penney, Rhys DO Jones This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8519494/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Target-mediated drug distribution (TMDD) is typically classified by accelerated removal of drug after serum concentration drops below a critical level. Susceptible drugs would be dosed to a schedule that maintains exposure above this level, where concentration drops monoexponentially. Out-dosing TMDD often implies that target binding is saturated or degraded. T-cell engagers and other biologics are often given with low dosages which make out-dosing TMDD unrealistic, yet are also typically observed to have monoexponential degradation. It can be challenging to determine whether such a concentration-time relationship is due to TMDD or standard non-specific (intrinsic) routes of clearance, and more so to scale this clearance from preclinical settings, as TMDD-driven clearance may not scale allometrically like intrinsic clearance. In this work, we derived an algebraic expression for the proportion of clearance that is target-mediated or intrinsic, which requires only the intrinsic half-life and the target receptor's concentration, turnover rate and binding affinity for the drug. We further show that the typical transition from monoexponential decline of serum concentrations to accelerated, target-driven clearance occurs at concentrations given by two expressions in those same parameters. We apply the equations to published data for monoclonal antibodies and T-cell engagers, finding that we consistently characterise their clearance as expected. These expressions can be used to determine if a drug's clearance would be expected to be driven by target-mediated or non-specific routes at pharmacologically active concentrations, and hence how to accurately translate pharmacokinetic properties from preclinical species to human, a process that is essential for drug development. Full Text Additional Declarations Competing interest reported. All authors are employees and shareholders in AstraZeneca. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Mar, 2026 Reviews received at journal 15 Mar, 2026 Reviewers agreed at journal 23 Feb, 2026 Reviews received at journal 27 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers invited by journal 18 Jan, 2026 Editor assigned by journal 06 Jan, 2026 Submission checks completed at journal 06 Jan, 2026 First submitted to journal 05 Jan, 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-8519494","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":577534844,"identity":"e0faaf86-574b-4175-8fce-f54e8e91f470","order_by":0,"name":"Liam V Brown","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYBACPmYgwdgAYjIfIE4LG0ILWwIDQwIxWhjgWngMiNTCzvx0A+OOe3IGt3s+fvz54568fHvvwQc/ahjk+cWwu5SNmc3sBuOZYmODO2c3S/MkFBs29pxLNuw5xmA4czZ2O4F+AWppS0jcdiN3gzRDQgJjs0SOmTTQwQkGt3FpYf8G1ZLz+OePhAT7Nvk35r8Z/uHTwgOzJYdNgichIbFHgseMmbENr5ayG4lnEoztb6SZWfOkJSTP4Mkxluztk8DpF37+49tufNyRICc5I/nxzR82Cbbz288YfvjxzUaeXxq7FjDAJiWBW/koGAWjYBSMAoIAAM6/WU+UngmnAAAAAElFTkSuQmCC","orcid":"","institution":"AstraZeneca (United Kingdom)","correspondingAuthor":true,"prefix":"","firstName":"Liam","middleName":"V","lastName":"Brown","suffix":""},{"id":577534845,"identity":"5b1ed618-3ac9-43ff-9408-0c85d1d6d28e","order_by":1,"name":"Alberto Ippolito","email":"","orcid":"","institution":"AstraZeneca (United Kingdom)","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Ippolito","suffix":""},{"id":577534846,"identity":"34f42085-b582-4c6f-ba02-4697b28cfea4","order_by":2,"name":"Mark Penney","email":"","orcid":"","institution":"AstraZeneca (United Kingdom)","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Penney","suffix":""},{"id":577534847,"identity":"f3473fb3-df84-4ddf-820c-d2494b116ea2","order_by":3,"name":"Rhys DO Jones","email":"","orcid":"","institution":"AstraZeneca (United Kingdom)","correspondingAuthor":false,"prefix":"","firstName":"Rhys","middleName":"DO","lastName":"Jones","suffix":""}],"badges":[],"createdAt":"2026-01-05 09:38:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8519494/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8519494/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100744742,"identity":"5f950bfd-9f91-4e64-a118-d3eb2c2a77b9","added_by":"auto","created_at":"2026-01-21 03:01:41","extension":"json","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6300,"visible":true,"origin":"","legend":"","description":"","filename":"603d8696d0994fd3877e1a91469a176d.json","url":"https://assets-eu.researchsquare.com/files/rs-8519494/v1/70217a28a35943aeb39468bb.json"},{"id":100804059,"identity":"51fc9fb6-c0b4-4177-abe5-d7fb967eabdb","added_by":"auto","created_at":"2026-01-21 14:35:41","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2066208,"visible":true,"origin":"","legend":"","description":"","filename":"submissionjpkpd.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8519494/v1_covered_3f3b64c9-94a8-4d3c-a0be-630f1cb432f9.pdf"}],"financialInterests":"Competing interest reported. All authors are employees and shareholders in AstraZeneca.","formattedTitle":"A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"journal-of-pharmacokinetics-and-pharmacodynamics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jopa","sideBox":"Learn more about [Journal of Pharmacokinetics and Pharmacodynamics](http://link.springer.com/journal/10928)","snPcode":"10928","submissionUrl":"https://submission.nature.com/new-submission/10928/3","title":"Journal of Pharmacokinetics and Pharmacodynamics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8519494/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8519494/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Target-mediated drug distribution (TMDD) is typically classified by accelerated removal of drug after serum concentration drops below a critical level. Susceptible drugs would be dosed to a schedule that maintains exposure above this level, where concentration drops monoexponentially. Out-dosing TMDD often implies that target binding is saturated or degraded. T-cell engagers and other biologics are often given with low dosages which make out-dosing TMDD unrealistic, yet are also typically observed to have monoexponential degradation. It can be challenging to determine whether such a concentration-time relationship is due to TMDD or standard non-specific (intrinsic) routes of clearance, and more so to scale this clearance from preclinical settings, as TMDD-driven clearance may not scale allometrically like intrinsic clearance.\n\nIn this work, we derived an algebraic expression for the proportion of clearance that is target-mediated or intrinsic, which requires only the intrinsic half-life and the target receptor's concentration, turnover rate and binding affinity for the drug. We further show that the typical transition from monoexponential decline of serum concentrations to accelerated, target-driven clearance occurs at concentrations given by two expressions in those same parameters. We apply the equations to published data for monoclonal antibodies and T-cell engagers, finding that we consistently characterise their clearance as expected. These expressions can be used to determine if a drug's clearance would be expected to be driven by target-mediated or non-specific routes at pharmacologically active concentrations, and hence how to accurately translate pharmacokinetic properties from preclinical species to human, a process that is essential for drug development.","manuscriptTitle":"A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-21 03:01:19","doi":"10.21203/rs.3.rs-8519494/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T01:16:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-15T20:27:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"103336472866595581723762169698358702923","date":"2026-02-23T11:54:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-27T20:56:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169279033913824511600445400354382696811","date":"2026-01-20T14:16:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-19T04:15:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-06T13:08:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-06T13:07:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Pharmacokinetics and Pharmacodynamics","date":"2026-01-05T09:27:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-pharmacokinetics-and-pharmacodynamics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jopa","sideBox":"Learn more about [Journal of Pharmacokinetics and Pharmacodynamics](http://link.springer.com/journal/10928)","snPcode":"10928","submissionUrl":"https://submission.nature.com/new-submission/10928/3","title":"Journal of Pharmacokinetics and Pharmacodynamics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1d4618c3-b281-4fc8-92f2-19389b568122","owner":[],"postedDate":"January 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T04:55:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-21 03:01:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8519494","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8519494","identity":"rs-8519494","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}