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

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.