Pediatric Oral Cavity Physiologically Based Pharmacokinetic Model to Predict Pharmacokinetics of Mucoadhesive Atropine Gel to Treat Sialorrhea

Pediatric Oral Cavity Physiologically Based Pharmacokinetic Model to Predict Pharmacokinetics of Mucoadhesive Atropine Gel to Treat Sialorrhea | 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 Pediatric Oral Cavity Physiologically Based Pharmacokinetic Model to Predict Pharmacokinetics of Mucoadhesive Atropine Gel to Treat Sialorrhea Madison Parrot, Nancy Murphy, Joseph Rower, Christopher Reilly, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8780503/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 Sialorrhea is a debilitating condition that significantly impairs quality of life in children with neurodevelopmental disorders, including cerebral palsy and neuromuscular disorders, yet safe and effective pharmacologic treatment options remain limited. Although atropine is widely used for sialorrhea, it is most commonly used off-label as ophthalmic drops administered intraorally; this approach is constrained by poor mucosal retention, frequent dosing, risk of medication errors, and systemic anticholinergic adverse effects. To address these limitations, a novel mucoadhesive atropine oral gel (0.01% weight/weight (w/w)) was developed to enhance intraoral residence time and local absorption while reducing systemic exposure variability. The pharmacokinetics and safety of the atropine gel were evaluated in a Phase I clinical trial in healthy adults, which informed the development and validation of a physiologically based pharmacokinetic (PBPK) model incorporating a mechanistic oral cavity framework. The oral cavity PBPK model accounts for salivary flow, mucosal absorption, swallowing, and saliva-tissue exchange across six compartments, enabling predictions of local and systemic exposure. Pediatric PBPK simulations were scaled from the adult model using Population Estimates for Age-Related Physiology™ (PEAR Physiology™) to support model-informed dose selection. Simulations identified a minimum pediatric dose range of 0.25 mg/kg/day, with twice-daily dosing to maintain plasma concentrations within the established minimum effective and maximum tolerated concentration range. These results demonstrate the utility of PBPK modeling in model-informed drug development and pediatric dose optimization to support further clinical development of mucoadhesive atropine gel as a safer alternative to off-label atropine eye drops for the management of pediatric sialorrhea. Atropine pharmacokinetics sialorrhea excessive salivation neurodevelopmental disorders pediatrics Full Text Additional Declarations No competing interests reported. Supplementary Files S1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 31 Mar, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 18 Mar, 2026 Reviews received at journal 18 Mar, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers invited by journal 13 Feb, 2026 Editor assigned by journal 04 Feb, 2026 Submission checks completed at journal 04 Feb, 2026 First submitted to journal 03 Feb, 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. 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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-8780503","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":592470065,"identity":"46b521d6-2442-4fff-8565-a8010a849ec2","order_by":0,"name":"Madison Parrot","email":"","orcid":"","institution":"University of Utah","correspondingAuthor":false,"prefix":"","firstName":"Madison","middleName":"","lastName":"Parrot","suffix":""},{"id":592470066,"identity":"c8de300b-7a71-4cb1-8436-5420708402a8","order_by":1,"name":"Nancy Murphy","email":"","orcid":"","institution":"University of Utah 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