Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers

Abstract

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off‐label treatment to manage sialorrhea. However, the off‐label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off‐label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single‐dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two‐compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL⁻¹, respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h⁻¹. Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well‐tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sialorrhea affects the quality of life of patients with neurodevelopmental disorders and yet treatment options are limited. Although it has been established that providers prescribe atropine eye drops for administration to the oral mucosa, this off‐label use is limited by non‐standardized dosing, low residential time in the mouth, medication errors, the need for frequent administration, and systemic side effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluates the safety and pharmacokinetics (PKs) of atropine gel after topical administration to the oral mucosa in healthy human volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides detailed PK characterization of an oral atropine mucoadhesive gel as well as its safety profile. This phase I study can be used in future phase II clinical trials to evaluate efficacy.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The development of an oral atropine gel allows for improved treatment accessibility, standardized dosing recommendations, increased residential time in the oral cavity, minimized systemic side effects, and addressing an unmet clinical need for persons with sialorrhea.

INTRODUCTION

Sialorrhea is excessive salivation that affects the quality of life of children with neurodevelopmental disorders, including cerebral palsy and dystonia. ¹ , ² , ³ , ⁴ Consequences of excessive salivation are both psychological and psychosocial with stigma surrounding hygiene, cosmesis, and social isolation, as well as physical with perioral skin excoriation, infection, sleep disruption, ⁵ and speech impairment. ⁵ Posterior drooling can lead to recurrent lower respiratory infections and progressive lung injury. ⁶ Despite excessive salivation affecting ~22%–40% of children with cerebral palsy, ¹ management options are lacking. ⁵ , ⁷ Additionally, for patients of all ages, up to 80% of those with Parkinson's disease and 30% of those with amyotrophic lateral sclerosis experience excessive salivation. ⁸

The current strategies to manage sialorrhea include nonpharmacologic and pharmacologic options. The nonpharmacologic options include rehabilitation and surgical approaches. Physical, occupational, and speech language therapists target oral motor skills that may improve symptoms of sialorrhea. ⁹ Rehabilitative therapies can be effective, particularly when combined with other treatment methods. Additionally, surgery (submandibular gland excision, submandibular gland duct rerouting, sublingual gland excision, submandibular gland duct ligation, parotid duct rerouting, and parotid duct ligation) ¹⁰ or radiation therapy (external beam radiation therapy) ⁸ of the salivary glands have been proven efficacious, but are invasive with a long recovery time and have risks of facial nerve injury.

Pharmacological treatment options for sialorrhea involves the use of anticholinergic agents, including atropine, glycopyrrolate, scopolamine, and benztropine. ³ , ¹¹ , ¹² Anticholinergic agents block cholinergic muscarinic receptors that are responsible for saliva production. Widely used anticholinergic medications are atropine, scopolamine, and glycopyrrolate. Glycopyrrolate is approved by the US Food and Drug Administration (FDA) for the treatment of sialorrhea in pediatric patients with neurological disorders. ¹³ However, glycopyrrolate use is limited by its side effects including dryness of the mouth, urinary retention, constipation, blurred vision, and effects on the central nervous system activity. ¹¹ Botulinum toxin A is an effective treatment for sialorrhea when injected into the parotid and submandibular glands, but requires injections every 3–4 months and is cost‐prohibitive for many patients. ¹¹ , ¹⁴

In addition to available anticholinergic agents, off‐label use of atropine eye drops to treat sialorrhea is mainstay therapy in institutions across the world. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² However, this off‐label treatment is limited by the need for frequent administration due to lack of retention on oral mucosa, ¹⁸ incidence of dosing and medication errors, ²³ and systemic side effects, such as tachycardia, fever, tremors, and restlessness. ²⁴ Several case reports described that the dosing and medication errors with atropine eye drops were due to accidental ingestion of the entire contents of the atropine eye drop bottle by the patients. ²⁴ , ²⁵ To address these limitations associated with off‐label use of atropine eye drops, we developed a mucoadhesive oral gel formulation of atropine. Mucoadhesive atropine gel for use on the oral mucosa may reduce dosing errors associated with off‐label use of atropine eye drops. The mucoadhesive properties of Carbopol, used in the topical oral gel formulation in this study have been demonstrated in a multi‐institutional, randomized, double‐blind, placebo‐controlled clinical trial. ²⁶ Carbopol's mucoadhesive ability is through van der Waals force interactions, hydrogen bonds, interdiffusion, and secondary bond formation between Carbopol and glycoproteins in mucin. ²⁷

The mechanism of action for mucoadhesive atropine gel can be explained through two distinct pathways. First, it may exert a direct anticholinergic effect at the acinar cells (cells that produce saliva) of the sublingual salivary glands, which constitute one of the three major salivary glands. ²⁸ Additionally, local administration of atropine eye drops in the sublingual region could also influence minor salivary glands dispersed throughout the oral submucosa. ²⁸ Second, the sublingual mucosa boasts a robust network of blood vessels, facilitating the rapid systemic absorption of atropine. ²⁹ This, in turn, enables atropine to exert its anticholinergic effects on all three major salivary glands. In theory, the novel atropine gel will fill a clinical need for atropine for the management of sialorrhea, specifically in the pediatric population.

The first step for clinical translation of the atropine gel formulation is to conduct a pharmacokinetic (PK) study in healthy volunteers. This clinical trial provides important foundational PK data that can be used to inform further clinical development. This pivotal step offers perspective on how the atropine oral gel is absorbed, distributed, metabolized, and excreted. PK data are also essential to support regulatory submissions to health authorities, such as the FDA. Ultimately, the clinical trial advances the atropine gel toward broader clinical applications with the goal of addressing specific unmet medical needs of persons with sialorrhea.

METHODS

Study design

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, Salt Lake City, Utah. The study was registered on clinicaltrials.gov (identifier: NCT05164367). ³⁰

Ten participants completed the study with a single administered dose of 1 g of 0.01% (w/w) atropine. All participants self‐administered 1 g of atropine gel that contains (0.1 mg of atropine) to the oral mucosa. For each participant, 1 g of atropine gel was preweighed by the Investigational Drug Services (IDS) pharmacy, University of Utah, and provided in sterile syringes. Participants were trained on self‐administration by a licensed pharmacist. Heart rate and oxygen saturation levels were measured every hour until 8 h, then again at 24 h, and blood pressure was measured at 0, 2, 4, 6, 8, and 24 h during the study. Cardiac function would be monitored using electrocardiogram if tachycardia (heart rate > 90 beats per minute) was observed, although this measure was not necessary through the course of the study. A schematic of the trial design is shown in Figure 1.

FIGURE 1.

Study flow diagram. HPLC–MS/MS, high‐performance liquid chromatography–tandem mass spectrometry; NCA, noncompartmental analysis; PK, pharmacokinetic.

All participants provided written informed consent and went through a medical history review of current and previous medication use. After medical history review, participants underwent physical assessment to determine baseline vital signs (including blood pressure, pulse rate, respiratory rate, and temperature), to ensure that participants are in a healthy condition to participate in the study. On the day prior to or of atropine administration, each participant underwent a screening assessment that included a questionnaire for coronavirus disease (COVID) screening.

After administration of the study drug product, a series of timed blood samples (0, 5, 10, 15, 30, and 60 min, and 2, 4, 6, 8, and 24 h, 7 mL each timepoint) were collected in vacutainers with an EDTA anticoagulant, and plasma were separated by centrifugation. Isolated plasma was stored in polypropylene cryovials at −80°C until analysis at the Center for Human Toxicology.

Study participants

Participants were healthy male or nonpregnant female adults between 18 and 50 years of age. The sample size for this study was determined based on the number of subjects needed to derive PK profiles and was not sized for any statistical inferences. Participants were excluded from the study if they met the following criterion: (1) female subjects who were pregnant or nursing at the time of screening; (2) underwent chemotherapy or radiotherapy treatment within the last 3 months; (3) exhibited deforming lesions of the oral cavity; (4) experienced previous head and/or neck radiotherapy; (5) history of hypersensitivity reaction toward atropine and/or Carbopol 974 NF or any carbomers; (6) experiencing heart conditions such as congenital heart disease, heart failure, coronary heart disease, myocardial infarction, and arrhythmia; (7) experiencing acute glaucoma that may be exacerbated with atropine administration; (8) with partial pyloric stenosis or other diseases related to gastrointestinal obstruction; (9) diagnosed with urinary retention; (10) have been treated with any other investigational drug during the 30 days prior to enrollment into the study; (11) receiving anticholinergic medications at baseline visit; (12) receiving immunosuppression; (13) actively being treated for an infection; (14) have a history of salivary gland obstruction or stones; (15) have a history of chronic lung disease or chronic obstructive pulmonary disease; (16) have an artificial airway (tracheostomy); and (17) taking monoamine oxidase inhibitors.

Atropine gel formulation

Atropine sulfate monohydrate, United States Pharmacopeia (USP; Lot #2003110007) for human use was purchased from Letco Medical LLC. Carbopol 974 NF for human use was purchased from Lubrizol Corporation. The USP grade sterile water for injection and sodium hydroxide was purchased from commercial vendors by the IDS pharmacy, University of Utah Hospitals and Clinics, Salt Lake City, Utah. The atropine gel was prepared by compounding pharmacists at the IDS Pharmacy, University of Utah Hospitals and Clinics according to USP 797 guidelines. The step‐by‐step procedure for formulation of the atropine oral gel is described in File S1.

The gel formulation is comprised of atropine and carbomer 974P polymer (Carbopol 974 NF). Atropine is present in the gel at an amount of 0.01% by weight. The gel pH is adjusted using sodium hydroxide solution to be 7.0. Whereas atropine is an FDA drug that is used clinically, this is the first described use of the novel oral gel formulation (Patent Application WO2023076698A1 and US 2023/0149306 A1). ³¹ , ³² The gel was evaluated for physical and chemical stability at room temperature and under refrigeration for 1 week. The atropine gel was clear without any visible particles, aggregates, or precipitates, and the atropine content did not change. Microbiological stability and batch stability were evaluated for 30 days (at room temperature and under refrigeration), and no microbial growth was observed. The details of the chemical and microbial stability studies are provided in File S2.

Study assessments

Pharmacokinetics

A total of 11 blood samples of 7 mL each were collected from each participant for PK analysis. Samples are collected via venipuncture at 0 mins (predose), 5 mins, 10 mins, 15 mins, 30 mins, and 60 mins, and 2 h, 4 h, 6 h, 8 h, and 24 h postdose.

Measurement of atropine concentrations in plasma samples

Plasma samples were extracted using liquid–liquid extraction under basic conditions. A validated high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS) assay was used to measure atropine concentrations in the collected samples. HPLC‐MS/MS was accomplished with a ThermoScientific Accela HPLC autosampler and pump interfaced with a ThermoScientific TSQ Vantage triple quadrupole mass spectrometer. Chromatographic separation was performed on a Phenomenex Kinetix Biphenyl column (2.1 × 50 mm, 1.7 μm particle size) using gradient elution with a cycle time of 7 min per injection. The lower limit of quantification (LLOQ) is 0.01 ng/mL.

Quality control (QC) performance (accuracy and precision) was within 20% at three concentrations (0.03, 0.15, and 1.5 ng/mL) across method qualification (2 batches of 6 replicate QCs at each concentration) and sample analysis batches. Specifically, intra‐day accuracy (calculated as % difference from nominal) was between 8.9% and 16.1% (low QC), 2.8 and 5.7% (medium QC), and 1.3 and 3.4%; while inter‐day accuracy was 12.5%, 4.2%, and 2.4% for the low, medium, and high QC, respectively. Intra‐ and inter‐day precision (calculated as %coefficient of variation) was within 6.2%, 3.7%, and 2.7% for the low, medium, and high QC, respectively. Preliminary evaluation of stock and matrix stability under various conditions (bench top, freeze–thaw, 1‐month storage of stock solutions and QCs) found no evidence of atropine degradation under any condition. Complete details for the LC–MS/MS method used to measure atropine in plasma samples are provided in File S3.

Safety

Safety assessments included a review of medical history, review of adverse events, pregnancy test (for women of childbearing age), clinical laboratory evaluations, vital signs, and physical examinations. The list of clinical laboratory evaluations performed for each participant before and after drug administration are provided in File S4.

Pharmacokinetic analysis

Descriptive statistics were used for baseline and demographic characteristics, safety data, and PK parameter estimates. Plasma PK parameters except absorption rate constant (k _a) were calculated using the noncompartmental analysis (NCA) with PKanalix version 2021R1 (Antony, France, Lixoft SAS, 2021, http://lixoft.com/products/PKanalix/) software. The area under the curve (AUC) was calculated using the Linear Trapezoidal Linear method of PKanalix. The k _a was calculated using a compartmental analysis approach with an oral extravascular two‐compartment model with no delays; initial model parameters were manually adjusted to provide best fit and match parameters from the NCA.

The PK parameters AUC versus time curve from 0 to the last timepoint t measured (AUC_0–t ), AUC versus time curve from 0 to infinity (AUC_0–∞), maximum concentration (C _max), time to reach C _max (T _max), half‐life (t _1/2), and terminal elimination rate constant (k _el) are calculated using PKanalix version 2021R1. For the calculation of AUC_0–t and AUC_0–∞, a concentration of zero is assigned to each sample at time = 0 (predose). All other nonquantifiable or missing samples are assigned a value of “missing,” including any samples prior to the earliest quantifiable (LLOQ = 0.01 ng/mL). Mean plasma concentrations by treatment and time, for graphical and tabular presentation, are calculated using only the available quantifiable values.

The relative bioavailability (F _rel) was calculated for atropine gel versus sublingual administration of atropine eye drops ³³ using the equation provided in File S5. Using AUC to the last positive measurable concentration (AUC_last), F _rel was calculated in comparison to data reported by Schwartz et al. ³³ using NCA. Due to Schwartz et al. measuring concentration up to 8 h, an AUC_0–8 was calculated for the current study participants to enable a direct comparison of AUC_0–8 of Schwartz et al. and patient data.

Statistical analysis

One‐way analysis of variance (ANOVA) with Bonferroni's multiple comparison test was calculated using GraphPad Prism version 10.0.2 for Windows. One‐way ANOVA was applied for heart rate, blood pressure ratio, and oxygen saturation of each patient between the baseline value and the value at each time interval observed (0–8 h) during the study.

RESULTS

Study population

Ten participants met the inclusion and exclusion criteria and were enrolled in the study and all 10 participants completed the study. The demographic characteristics of the study participants are summarized in Table 1. Adverse effects, including deviation from baseline heart rate, blood pressure, or oxygen saturation, were not observed in any participants.

TABLE 1.

Demographics of participants in the trial.

Variable	Median	Range	IQR
Age, years	29.5	20–41	11.75
Height, cm	170.15	152.4–190.5	12.4
Weight, kg	80.5	56.5–128.4	28.88

Race	Number	Percent
White	8	80
Hispanic/Latinx	2	20

Sex	Number	Percent
Female	7	70
Male	3	30

Abbreviation: IQR, interquartile range.

Pharmacokinetics

The individual plasma concentrations versus time curves for each participant after administration of 1 mg atropine are provided in File S6. The mean plasma concentration versus time curve displaying biphasic PK is shown in Figure 2. The absorption phase lasts until ~1.5 h after administration. The linear regression of the terminal phase and R ² value for all 10 participants are shown in File S7.

FIGURE 2.

Mean plasma concentration versus time profiles of all healthy volunteer patient population (n = 10) after single atropine gel administration within the first 8 h of the study (red) and individual data (blue).

Apparent total body clearance (CL/F) after extravascular administration ranges between 95.3 and 205 L/h with a median of 146 L/h. V_d,ss = V/F ranges between 396 and 975 L with a median value of 638 L. The C _max ranges from 0.083 to 0.21 ng/mL with a median of 0.14 ng/mL. The T _max ranges from 1 to 2 h with an average of 1.6 h. AUC_0–24 ranges from 0.4 to 0.87 h ng/mL with a median value of 0.59 h ng/mL. The t _1/2 of the oral gel was 3.02 h. The k _el has a median value of 0.24 h⁻¹. The k _a has a median value of 0.4 h⁻¹. A summary of PK parameters can be found in Table 2.

TABLE 2.

PK parameters of 0.1 mg oral atropine gel.

PK parameter	Value
CL/F (L/h)	146.35
C max (ng/mL)	0.14
T max (h)	1.6
t 1/2 (h)	3.02
V/F (L)	637.51
AUC0–24 (h*ng/mL)	0.59
k el (h−1)	0.24
k a (h−1)	0.4

Abbreviations: AUC_0–24, 0–24‐hour area under the concentration‐time curve; CL/F, apparent total body clearance; C _max, maximum plasma concentration; k _a, absorption rate constant; k _el, terminal elimination rate constant; PK, pharmacokinetic; T _max, time to C _max; t _1/2, half‐life.

The dose adjusted F _rel of atropine gel formulation is 84% and 44.9% when compared to the 0.5 mg and 1 mg sublingual solution, respectively (File S5). The F _rel is measured from 0 to 8 h. The AUC_0–∞ had a mean value of 0.74 h·ng·mL⁻¹. Absolute bioavailability (F _abs) calculated with AUC to the last quantifiable data point (AUC_last) and AUC_0–∞ values from previously demonstrated intravenous injections of atropine ³³ , ³⁴ , ³⁵ are shown in Table 3. Mucoadhesive gel formulation reduces the overall bioavailability when compared to sublingual atropine eye drops.

TABLE 3.

F _abs of summary patient data using AUC_last and AUC_0‐∞ values in comparison to four i.v. references.

i.v, reference	AUClast	AUC0–∞
Hinderling 1.35 mg 32	0.484	0.568
Hinderling 2.15 mg 32	0.513	0.439
Schwartz 31	0.527	0.588
Adams 33	0.110	0.206

Abbreviations: AUC_0‐∞, area under the concentration versus time curve from 0 to infinity; AUC_last, AUC to the last positive measurable concentration; F _abs, absolute bioavailability.

A clinical trial involving two sublingual doses of 0.5 mg and 1 mg ophthalmic solution completed by Schwartz et al. provides an adequate comparison of atropine eye drops to the oral gel. PK comparisons of sublingual administration of atropine eye drops, i.v. administration of atropine, and oral administration of atropine gel are summarized in Table 4. As expected, i.v. administration of atropine showed the highest C _max and AUC_0–∞ as well as the lowest T _max and k _el. The t _1/2 of atropine for all administration routes and doses are comparable, around 3 h. The median C _max for the oral gel of 0.14 ng/mL displays low systemic concentration of atropine. After dose normalization, the C _max of the oral gel is 1.4 × 10⁻⁶ mg/mL. Compared to the two sublingual doses of 1 mg and 0.5 mg, C _max was 1.46 × 10⁻⁶ and 1.47 × 10⁻⁶ mg/mL after dose normalization, respectively. ³³ The C _max is lowest for the oral gel, albeit comparable to the sublingual doses. The AUC_0–∞ is of particular interest because of its representation of total drug exposure. For the oral gel, AUC_0–∞ = 7.4 × 10⁻⁶ h·ng·mL⁻¹. For the sublingual saline solutions, AUC_0–∞ = 8.24 × 10⁻⁶ and 7.87 × 10⁻⁶ h·ng·mL⁻¹ for the 0.5 mg and 1 mg doses, respectively. ³³

TABLE 4.

Comparison of participant numbers and PK parameters calculated using PKanalix NCA for sublingual atropine eye drops at 0.5 and 1 mg doses, i.v. atropine administration at 1 mg dose, and oral atropine gel administration at 0.1 mg dose.

Parameter	Schwartz sublingual (0.5 mg)	Schwartz sublingual (1 mg)	Schwartz i.v. (1 mg)	Oral gel patient (0.1 mg)
Participants (N)	12	12	12	10
AUC0–∞/dose (h·mg·mL−1)	8.24 × 10−6	7.87 × 10−6	12.6 × 10−6	7.4 × 10−6
CL/F (mL·min−1)	1800.8 a	2098.8 a	N/A	2425.99
C max/dose (mg·mL−1)	1.46 × 10−6	1.47 × 10−6	18.2 × 10−6	1.4 × 10−6
k el (h−1)	0.28	0.26	0.23	0.24
T max (h)	1.99	2.01	0.039	1.6
t 1/2 (h)	2.93 a	2.86 a	2.99 a	3.02

Note: AUC_0–∞ and C _max are dose normalized values.

Abbreviations: AUC_0–∞, area under the concentration versus time curve from 0 to infinity; CL/F, apparent total body clearance; C _max, maximum plasma concentration; k _el, terminal elimination rate constant; NCA, noncompartmental analysis; PK, pharmacokinetic; T _max, time to C _max; t _1/2, half‐life.

^a Values reported by Schwartz et al.

Safety and tolerability

Heart rate for each participant was measured every hour for up to 8 h after administration of atropine oral gel. The heart rate values for each participant are provided in Figure 3. One‐way ANOVA was applied between the baseline value of each patient (before administration) and the value at each time interval during the study. All 10 participants showed highly insignificant variation in heart rate (p = 0.9529). Therefore, after administration of the oral atropine gel, there is no statistically significant difference in heart rate at any measured timepoint for all participants (p > 0.05). The absence of any changes in heart rate, particularly instances of tachycardia, is especially noteworthy given the reported cases of tachycardia. ³⁶ , ³⁷ , ³⁸ After a one‐way ANOVA for blood pressure (ratio of systolic to diastolic arterial pressure) and oxygen saturation, the values for p = 0.096 and 0.442, respectively. Similar to heart rate, these data indicate that each patient's blood pressure and oxygen saturation was not significantly different after administration of oral atropine gel. Graphs of blood pressure and oxygen saturation at the time of and after oral atropine gel administration can be seen in File S8. Additionally, there were no local side effects reported by participants. In addition, clinical laboratory parameters comprehensive metabolic panel, kidney profile, complete blood count with platelet counts and auto differential, estimated glomerular filtration rate did not change before and after administration of atropine gel in all study participants.

FIGURE 3.

Graphical representation of heart rate 0–8 h after oral gel atropine administration for all patients (n = 10). One‐way ANOVA was applied to heart rate from baseline (0 h) to each timepoint through 8 h. ANOVA, analysis of variance; BPM, beats per minute; HR, heart rate.

DISCUSSION

In this study, for the first time, we report the PK of atropine gel administered to the oral mucosa in healthy human volunteers. The PK data from this study will be applicable to future efficacy and special population trials.

Sublingual use of atropine eye drops has been proven to be effective. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ³⁹ However, their off‐label use is limited by medication errors ²⁴ and low residence time. Reformulated atropine gel for oral use can further improve the safety and efficacy of treatment. Higher residence time on the oral mucosa due to the formulation of the oral gel is likely responsible for the more localized delivery and, therefore, lower plasma concentration of atropine. However, future studies with appropriate experimental models are needed to confirm that higher residence time of the atropine gel will improve its local activity. A median T _max of 1.6 h for the oral gel displays a standard time to the maximum concentration, comparable to calculated values for the sublingual eye drops which had a T _max of 1.99 and 2.01 h for the 0.5 mg and 1 mg doses respectively. Saarnivaara et al. reports T _max = 2 h for oral administration and 0.5 h for i.m. administration. ⁴⁰ The initial absorption phase of the atropine gel is slow (~1.5 h) which demonstrates the long residency time on the oral mucosa. The small k _a = 0.4 h⁻¹ indicates slow absorption into the bloodstream. For sublingual administration, with a 0.5 mg dose, k _a = 0.625 h⁻¹. ³² Localized use of atropine and quick onset of action is hypothesized to have better efficacy for sialorrhea than other administration routes. Future efficacy studies are necessary to explore this hypothesis.

Atropine PK has been evaluated orally, i.v., i.m., and sublingually, but never in the form of an oral gel. ³³ , ³⁴ , ³⁵ , ⁴¹ , ⁴² The atropine oral gel has lower plasma concentrations of atropine than any other administration route. The lower plasma concentrations will decrease adverse effects due to systemic exposure to atropine. A previous study by Rajpal et al. on the effect of atropine on heart rate showed an “extremely significant” increase in heart rate using an unpaired t‐test comparing the mean baseline heart rate to that after sublingual atropine administration. ⁴³ In another study conducted by Saarnivaara et al., ⁴⁰ i.m. administration of atropine in children, heart rate was statistically significantly higher after administration.

The calculated F _rel indicates lower bioavailability of the atropine gel formulation than both doses of atropine eye drops administered sublingually. This means there may be a more local effect (less systemic effect) of the atropine gel than sublingual administration of atropine eye drops at the respective doses. Sublingual administration involves placing the atropine drops under the tongue whereas the atropine gel is administered to a higher surface area of oral mucosa. Even with the increased surface area of administration with the atropine oral gel involving both buccal and sublingual areas, the bioavailability was still lower. The F _abs shows much less systemic circulation of the atropine gel than in comparison with i.v. administration. The t _1/2 of the oral gel is approximately equal to that of the i.v. and two doses of atropine ophthalmic solution administered sublingually.

The V _d = 637.5 L exceeds the volume of total body water which indicates the atropine is widely distributed in the body. For sublingual administration of eye drops, the low dose V _d = 423.7 L and high dose V _d = 496.7 L. ³² For i.v. administration of atropine, V _d = 210 L. ³³ For the oral gel, CL/F = 146.3 L/h, which is comparable to reported clearance values. Schwartz et al. ³³ reports mean CL/F of 108 L/h and 125.9 L/h after 0.5 mg and 0.1 mg atropine sulfate ophthalmic administration sublingually, which is expected.

This clinical trial showed that atropine gel (0.1 mg) after topical oral administration did not result in any local or systemic adverse events. However, systemic side effects like tachycardia, fever, tremors, and restlessness may be expected with atropine gel with increased dose. ²⁴ Although the self‐administration of gel to the oral mucosa may introduce variability between participants, the interindividual trends remained consistent. The ease of self‐administration in home and outpatient settings provides advantages over other routes of administration and increases patient compliance. This is promising for the use of the gel in a pediatric population. Future directives include: phase II efficacy trial in healthy adults, use physiologically‐based pharmacokinetic modeling with an oral compartment modeling to assist in the development (dosing regimen) of a pediatric clinical trial (phase IIa), and commercialization of the oral atropine gel for prescription use.

This study has limitations. The study participant population is primarily White, which is not representative of the average population. Using healthy volunteers is a limitation as the goal is to treat patients with sialorrhea; future phase IIa trials will provide more information. Another limitation is using a single dose; future multiple‐dose studies will inform the effects of the gel on the body over time. This atropine gel is intended to be administered multiple times to maintain a therapeutic level and a multiple dosing trial can provide information on accumulation and steady‐state concentrations.

Based on the results of this trial, atropine gel can be further evaluated for efficacy and eventual translation to the clinic. This novel oral atropine gel can fill a need for sialorrhea management without the need for off‐label use of atropine eye drops.

AUTHOR CONTRIBUTIONS

M.P. and V.Y. wrote the manuscript. M.P., B.Y., O.A., L.H., J.R., M.V., D.G., A.T., A.W., and V.Y. performed research. M.P. and V.Y. analyzed the data. H.G. N.M. and V.Y. designed the research.

FUNDING INFORMATION

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 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.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interests.

Supporting information

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Parrot M, Yathavan B, Averin O, et al. Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers. Clin Transl Sci. 2024;17:e13753. doi: 10.1111/cts.13753