(T1030-02-07) Pediatric Oral Cavity PBPK Model to Predict Pharmacokinetics of Mucoadhesive Atropine Gel to Treat Sialorrhea

Purpose: Sialorrhea, or excessive salivation, is a chronic and serious problem in children with cerebral palsy and neurodevelopmental disorders.^1-5 Sialorrhea occurs in up to 60% of children with cerebral palsy and has serious health consequences, including recurrent pulmonary infections and progressive lung disease.^6,7-9 Several clinical studies identified that sialorrhea reduced social interaction and self-esteem and concluded that sialorrhea significantly diminished the quality of life in children with cerebral palsy.<sup>10-17 The current management options for sialorrhea, such as surgical removal of salivary glands, botulinum toxin injections, and systemic anticholinergic medications, have several limitations, and there is no clear consensus on which management strategies are safe and effective.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 Although atropine eye drops are useful to manage sialorrhea, they have several drawbacks: 1) short residence time requiring frequent administration, 2) lack of optimal dosing guidelines, and 3) fatal medication errors. To address these limitations, we developed a mucoadhesive gel formulation of atropine using Carbopol 974® (US Patent Appl. No: US20230149306A1).18 Our mucoadhesive atropine gel may increase the residence time of atropine in the oral cavity, thereby reducing the frequency of administration and systemic adverse effects. We completed an FDA-approved Phase I study of atropine gel in adults and established the safety and PK profile. The purpose of this study is to develop a pediatric oral cavity physiologically based pharmacokinetic (PBPK) model using the PK data from Phase I study in adults and use the oral cavity PBPK model to develop an optimal dosing regimen of atropine gel in pediatric patients for a Phase II efficacy study.

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 software. The OCCATTM model has six physiological compartments: buccal, gingival, palate, top of the tongue, bottom of the tongue, and mouth floor. The OCCATTM PBPK model incorporates physiological parameters such as blood flow, surface area, thickness of epithelial and lamina propria layers of the oral cavity, basal saliva volume, and systemic uptake of the drug. The drug-specific input parameters of atropine for the adult oral cavity PBPK model are provided in Table 1. 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) physiology of GastroPlus®. The pediatric oral cavity PBPK model of atropine gel was used to simulate the PK of atropine gel at dose ranges from 0.1 to 0.8 mg/day in a virtual pediatric population (N=100) with an age range of 1-18 years. The optimal dose of atropine gel in pediatric patients for efficacy study was selected using the minimum efficacy target concentration of 1.46 ng/mL20 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 (Figure 1). The predicted PK parameters of atropine C_max, T_max, AUC_0-24h, and AUC_0-inf after administration to the oral cavity as a gel formulation were all within ±30% of the observed values. The average fold error (AFE) of atropine plasma concentrations in the adult model predicted vs. observed concentration was with the prespecified acceptance criteria of 0.5 to 2. The pediatric oral cavity PBPK model predictions of atropine gel at doses from 0.1 to 8 mg/day are shown in Figure 2. The simulations showed that for doses up to 8 mg/day 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.

Conclusion: 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, utilizing Phase I clinical data. The pediatric oral cavity PBPK model was successfully scaled from the adult model using PEARTM physiology. Based on the pediatric PBPK model, the dose range for atropine is 1-8 mg per day is safe and effective in pediatric patients with sialorrhea. The mucoadhesive gel formulation containing atropine may offer a superior alternative to the off-label utilization of atropine eye drops for managing sialorrhea. The data from this study will be useful for future Phase II clinical efficacy studies of atropine gel in pediatric sialorrhea patients with neurodevelopmental disorders.

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18. Yellepeddi VK, inventor; Compositions and Methods for Treating Sialorrhea. United States 2023.
19. Parrot M, Yathavan B, Averin O, et al. Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers. Clinical and Translational Science. 2024-03-01 2024;17(3)doi:10.1111/cts.13753
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22. Pharmacokinetics of Atropine Oral Gel. https://clinicaltrials.gov/study/NCT05164367?term=yellepeddi&rank=1

Acknowledgements: Authors declare no conflict of interests. This research was supported by Primary Children Hospital Foundation (PCHF) Grant awarded to Venkata Kashyap Yellepeddi. The research reported in this publication was supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR002538 and UM1TR004409. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study protocol was reviewed and approved by the FDA under an investigator-initiated investigational new drug (IND) application (IND#155751). The study protocol was also reviewed and approved by the Institutional Review Board (IRB), University of Utah (IRB #00144918). This study was a single-center, open-label, prospective PK trial conducted at the Utah Clinical and Translational Science Institute (CTSI), Salt Lake City, Utah. The study was registered on clinicaltrials.gov (identifier: NCT05164367).22


Table 1. Drug-specific input parameters for the adult and pediatric oral cavity PBPK model.


Figure 1. Adult oral cavity PBPK model predicted vs. Phase I observed data of atropine gel PK. The black line represents the adult oral cavity PBPK model predicted mean atropine plasma levels in virtual adult population (N=100). The red dark circles represent the observed individual atropine plasma concentrations at each timepoint from the Phase I PK study in healthy volunteers (N=10).


Figure 2. Box-whisker plots of pediatric oral cavity PBPK model predicted atropine PK in the virtual pediatric population (N=100) when administered different doses of atropine gel (0.1 to 8 mg/day). The box represents the 25th and 75th percentiles, while the line inside the box is the median, and the whiskers are the minimum and maximum Cmax values. The efficacy target (blue) represents the minimum dose to reduce sialorrhea by 50%. The safety target (red) represents the maximum tolerated dose before toxic effects are observed.</sup>