Pediatric oral cavity physiologically based pharmacokinetic model to predict pharmacokinetics of mucoadhesive atropine gel to treat sialorrhea.

Sialorrhea significantly impairs quality of life in children with neurodisabilities, including cerebral palsy, 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, an approach constrained by poor mucosal retention, frequent dosing, medication-error risk, and systemic anticholinergic adverse effects. To address these limitations, we developed a novel mucoadhesive atropine oral gel (0.01% weight/weight (w/w)) to enhance intraoral residence time and support controlled local and systemic exposure. 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 and evaluation of formulation-relevant determinants of intraoral absorption. 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 once or twice daily, with twice-daily dosing to maintain plasma concentrations within the established minimum effective and maximum tolerated concentration range. Collectively, this work demonstrates the utility of PBPK modeling as a translational tool to integrate formulation attributes, oral cavity physiology, and pediatric dose selection, and supports the clinical advancement of mucoadhesive atropine gel as a safer alternative to off-label intraoral atropine eye drops.