Objectives: Sialorrhea, or excessive salivation, is a chronic and serious problem in children with cerebral palsy (CP) and neurodevelopmental disorders.[1–5] Sialorrhea occurs in up to 60% of children with CP and has serious health consequences, including recurrent pulmonary infections and progressive lung disease.[6,7–9] Sialorrhea reduces social interaction and self-esteem, and can significantly diminish the quality of life in children with CP.[10–17] Current treatments are often invasive or poorly tolerated.[6] Due to ease of administration, limited side effect profile, and the rapidity of a drying effect, sublingual atropine eye drops are frequently used off-label to treat sialorrhea.[3] To improve upon this, we developed a mucoadhesive atropine gel (US Patent Appl. No: US20230149306A1) that increases oral residence time and reduces dosing frequency and side effects.[18] Following a completed FDA-approved Phase I trial confirming safety and pharmacokinetics (PK) in adults, this study aims to scale and verify an oral cavity physiologically-based pharmacokinetic (PBPK) model for pediatric use and develop an optimal dosing regimen for a Phase II efficacy trial.

Methods: The adult oral cavity PBPK model of atropine gel was developed using the Oral Cavity Compartmental Absorption and Transit (OCCATTM) module of GastroPlus®, SimulationsPlus, USA. The OCCATTM PBPK model has six compartments and specific oral parameters. The adult oral cavity model was optimized using the PK data obtained from our Phase I study of atropine gel in healthy adults.[19] The pediatric oral cavity PBPK model of atropine gel was scaled from the adult model using Population Estimates for Age-Related PhysiologyTM (PEAR PhysiologyTM) module of GastroPlus® and used to simulate the PK of atropine gel at dose ranges 0.003 to 0.222 mg/kg in virtual populations of children (N=1000) representing the following age groups: infants (29 days to < 2 years), children (2 to < 12 years), and adolescents (12 to 21 years). The optimal dose of atropine gel in pediatric patients for this efficacy study was selected using the minimum efficacy target concentration of 1.46 ng/mL[20] and maximum toxic target concentration of 61 ng/mL.[21]

Results: The adult oral cavity PBPK model of atropine gel accurately predicted the observed data from the Phase I PK study of atropine gel in adult healthy volunteers. The predicted PK parameters of atropine Cmax, Tmax, AUC0-24h, and AUC0-inf after administration to the oral cavity as a gel formulation were all within ±30% of the observed values. The pediatric oral cavity PBPK model simulations showed that for doses up to 0.222 mg/kg of atropine oral gel, atropine levels did not reach the maximum toxicity target level (61 ng/mL), and a minimum dose of 1 mg/day is required to reach the efficacy target (1.46 ng/mL) to see a 50% reduction in sialorrhea.

Conclusions: The mucoadhesive atropine gel was determined to be safe, with optimal PK, in a healthy adult population, as demonstrated by the Phase I clinical trial.19 The development and validation of the adult oral cavity PBPK model for atropine gel were successfully completed and validated and was successfully scaled to pediatrics. The dose range for atropine, 0.003 to 0.222 mg/kg, is safe in pediatric patients with sialorrhea.

By Madison Parrot , B.S., Nancy Murphy , Venkata Yellepeddi