Pharmacokinetics of Atropine Oral Gel

Cerebral Palsy Clinical Trial

Official title:

Single-Dose Pharmacokinetics of Atropine Oral Gel in Healthy Adults

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05164367
• Other study ID #: 144918
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: October 1, 2022
• Est. completion date: July 2024

Study information

• Verified date: November 2023
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the single-dose pharmacokinetics of atropine gel formulation after topical administration in the oral cavity of healthy adults.

Description:

This study is a single-dose, single-center, open-label study of the pharmacokinetics of atropine gel (0.01% w/w) after topical oral administration in healthy adults. Study participants will be recruited by Drs. Murphy, Darro, and Yellepeddi at the Center for Clinical and Translation Science (CCTS), University of Utah. Participants who meet eligibility criteria will be recruited in the study after signing informed consent. Each of the 10 participants will receive 1 gram of atropine gel (0.01% w/w) containing 0.1 mg atropine via self-administration of gel into the oral cavity. Dr. Yellepeddi is a licensed pharmacist in the State of Utah and will train subjects in the administration of atropine gel in the oral cavity. A series of timed blood samples (0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours, 7 mL each time point) will be collected in commercial tubes, and plasma will be separated by centrifugation. The plasma samples will be stored frozen until further analysis by the Center for Human Toxicology (CHT), University of Utah.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: July 2024
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Provide written informed consent and authorization.

2. Study participants must be able to complete consent, and all study evaluations written in the English language.

Exclusion Criteria:

1. Female subjects who are pregnant or nursing at the time of screening

2. Chemotherapy or radiotherapy treatment within the last three months

3. Severe renal impairment defined as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated using the CKD-EPI creatinine equation:

eGFR (mL/min/1.73 m2) = 141 x min(Scr/k, 1)a x max(Scr/k,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black]

Where,

1. k=0.7 if female

2. k=0.9 if male

3. a=-0.329 if female

4. a=-0.411 if male

5. min=The minimum of Scr/k or 1

6. max=The maximum of Scr/k or 1

7. Scr = serum creatinine (mg/dL)

4. Acute hepatitis in the prior 6 months, a prior history of cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure; and/or any of the following blood test results, for any individual, when assessed for eligibility:

1. Bilirubin > 3 x upper limit of normal (ULN). [ULN for bilirubin = 1.4 mg/dL]

2. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) > 3 x ULN values used by the laboratory performing the test. [ULN for AST = 40 U/L, ULN for ALT = 60 U/L]

3. Alkaline phosphatase (ALP) > 3 x ULN [ULN for ALP = 126 U/L)

5. Deforming lesions of the oral cavity

6. Previous head and/or neck radiotherapy

7. Patients with a history of hypersensitivity reaction towards atropine and/or Carbopol 980 NF or any carbomers

8. Patients with heart conditions such as congenital heart disease, heart failure, coronary heart disease, myocardial infarction, and arrhythmia

9. Patients with acute glaucoma that may be exacerbated with atropine administration.

10. Patients with partial pyloric stenosis or other diseases related to gastrointestinal obstruction.

11. Patients diagnosed with urinary retention

12. Treatment with any other investigational drug during the 30 days prior to enrollment into the study

13. Patients receiving anticholinergic medications at baseline.

14. Patients who are receiving immunosuppression

15. Patients who are actively being treated for an infection

16. Patients with a history of salivary gland obstruction or stones

17. Patients with a history of chronic lung disease or chronic obstructive pulmonary disease (COPD)

18. Patients with an artificial airway (tracheostomy)

19. Patient taking monoamine oxidase inhibitors

Related Conditions & MeSH terms

• Cerebral Palsy
• Sialorrhea

Intervention

Drug:
• Atropine sulfate gel (0.01%)
A research nurse will measure 1 gram of gel using a calibrated measuring spoon and will provide it to the participant for self-administration.

Locations

Country	Name	City	State
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
University of Utah

Country where clinical trial is conducted

United States, 

References & Publications (23)

Alcon (2018). Viscotears® Liquid Gel [carbomer (polyacrylic acid)] - Patient Information Leaflet

Allison RR, Ambrad AA, Arshoun Y, Carmel RJ, Ciuba DF, Feldman E, Finkelstein SE, Gandhavadi R, Heron DE, Lane SC, Longo JM, Meakin C, Papadopoulos D, Pruitt DE, Steinbrenner LM, Taylor MA, Wisbeck WM, Yuh GE, Nowotnik DP, Sonis ST. Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Cancer. 2014 May 1;120(9):1433-40. doi: 10.1002/cncr.28553. — View Citation

Azapagasi E, Kendirli T, Perk O, Kutluk G, Oz Tuncer G, Teber S, Cobanoglu N. Sublingual Atropine Sulfate Use for Sialorrhea in Pediatric Patients. J Pediatr Intensive Care. 2020 Sep;9(3):196-200. doi: 10.1055/s-0040-1708552. Epub 2020 Apr 7. — View Citation

De Simone GG, Eisenchlas JH, Junin M, Pereyra F, Brizuela R. Atropine drops for drooling: a randomized controlled trial. Palliat Med. 2006 Oct;20(7):665-71. doi: 10.1177/0269216306071702. — View Citation

Dias BLS, Fernandes AR, Maia HS Filho. Treatment of drooling with sublingual atropine sulfate in children and adolescents with cerebral palsy. Arq Neuropsiquiatr. 2017 May;75(5):282-287. doi: 10.1590/0004-282X20170033. — View Citation

Jones JM, Watkins CA, Hand JS, Warren JJ, Cowen HJ. Comparison of three salivary flow rate assessment methods in an elderly population. Community Dent Oral Epidemiol. 2000 Jun;28(3):177-84. doi: 10.1034/j.1600-0528.2000.280303.x. — View Citation

Keegan G, Smart J, Ingram M, Barnes L, Rees G, Burnett G. An in vitro assessment of bioadhesive zinc/carbomer complexes for antimicrobial therapy within the oral cavity. Int J Pharm. 2007 Aug 1;340(1-2):92-6. doi: 10.1016/j.ijpharm.2007.03.023. Epub 2007 Mar 24. — View Citation

Kelly HM, Deasy PB, Busquet M, Torrance AA. Bioadhesive, rheological, lubricant and other aspects of an oral gel formulation intended for the treatment of xerostomia. Int J Pharm. 2004 Jul 8;278(2):391-406. doi: 10.1016/j.ijpharm.2004.03.022. — View Citation

Lawrence R, Bateman N. Surgical Management of the Drooling Child. Curr Otorhinolaryngol Rep. 2018;6(1):99-106. doi: 10.1007/s40136-018-0188-2. Epub 2018 Mar 20. — View Citation

Leung JG, Schak KM. Potential problems surrounding the use of sublingually administered ophthalmic atropine for sialorrhea. Schizophr Res. 2017 Jul;185:202-203. doi: 10.1016/j.schres.2016.12.028. Epub 2016 Dec 30. No abstract available. — View Citation

Navazesh M, Christensen CM. A comparison of whole mouth resting and stimulated salivary measurement procedures. J Dent Res. 1982 Oct;61(10):1158-62. doi: 10.1177/00220345820610100901. No abstract available. — View Citation

Norderyd J, Graf J, Marcusson A, Nilsson K, Sjostrand E, Steinwall G, Arleskog E, Bagesund M. Sublingual administration of atropine eyedrops in children with excessive drooling - a pilot study. Int J Paediatr Dent. 2017 Jan;27(1):22-29. doi: 10.1111/ipd.12219. Epub 2015 Dec 27. — View Citation

Parkes J, Hill N, Platt MJ, Donnelly C. Oromotor dysfunction and communication impairments in children with cerebral palsy: a register study. Dev Med Child Neurol. 2010 Dec;52(12):1113-9. doi: 10.1111/j.1469-8749.2010.03765.x. Epub 2010 Aug 31. — View Citation

Protus BM, Grauer PA, Kimbrel JM. Evaluation of atropine 1% ophthalmic solution administered sublingually for the management of terminal respiratory secretions. Am J Hosp Palliat Care. 2013 Jun;30(4):388-92. doi: 10.1177/1049909112453641. Epub 2012 Jul 24. — View Citation

Rapoport A. Sublingual atropine drops for the treatment of pediatric sialorrhea. J Pain Symptom Manage. 2010 Nov;40(5):783-8. doi: 10.1016/j.jpainsymman.2010.02.007. Epub 2010 Jun 11. — View Citation

Regulatory Information for Carbopol®* 971P NF Polymer & Carbopol® 71G NF Polymer. file:///C:/Users/u0840209/Downloads/TDS-328_Carbopol_971P_71G_Regulatory_PH_Version%20(1).pdf

Reid SM, Johnson HM, Reddihough DS. The Drooling Impact Scale: a measure of the impact of drooling in children with developmental disabilities. Dev Med Child Neurol. 2010 Feb;52(2):e23-8. doi: 10.1111/j.1469-8749.2009.03519.x. Epub 2009 Oct 15. — View Citation

Reid SM, McCutcheon J, Reddihough DS, Johnson H. Prevalence and predictors of drooling in 7- to 14-year-old children with cerebral palsy: a population study. Dev Med Child Neurol. 2012 Nov;54(11):1032-6. doi: 10.1111/j.1469-8749.2012.04382.x. Epub 2012 Aug 9. — View Citation

Reid SM, Westbury C, Chong D, Johnstone BR, Guzys A, Reddihough DS. Long-term impact of saliva control surgery in children with disability. J Plast Reconstr Aesthet Surg. 2019 Jul;72(7):1193-1197. doi: 10.1016/j.bjps.2019.02.020. Epub 2019 Mar 2. — View Citation

Reid SM, Westbury C, Guzys AT, Reddihough DS. Anticholinergic medications for reducing drooling in children with developmental disability. Dev Med Child Neurol. 2020 Mar;62(3):346-353. doi: 10.1111/dmcn.14350. Epub 2019 Sep 8. — View Citation

Singla AK, Chawla M, Singh A. Potential applications of carbomer in oral mucoadhesive controlled drug delivery system: a review. Drug Dev Ind Pharm. 2000 Sep;26(9):913-24. doi: 10.1081/ddc-100101318. — View Citation

Speyer R, Cordier R, Kim JH, Cocks N, Michou E, Wilkes-Gillan S. Prevalence of drooling, swallowing, and feeding problems in cerebral palsy across the lifespan: a systematic review and meta-analyses. Dev Med Child Neurol. 2019 Nov;61(11):1249-1258. doi: 10.1111/dmcn.14316. Epub 2019 Jul 22. — View Citation

Zeller RS, Lee HM, Cavanaugh PF, Davidson J. Randomized Phase III evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in children with cerebral palsy or other neurologic conditions. Ther Clin Risk Manag. 2012;8:15-23. doi: 10.2147/TCRM.S26893. Epub 2012 Jan 25. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate pharmacokinetic parameter time to reach maximum plasma concentration (Tmax) in healthy adults to see if atropine will reach detectable concentrations in plasma following topical oral administration in gel formulation.	Calculate the pharmacokinetic parameter Tmax after topical oral administration of 0.01% atropine gel.	The Tmax will be evaluated at timepoints 0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours after administration of gel to the oral cavity.
Primary	Evaluate pharmacokinetic parameter time to reach maximum plasma concentration (Cmax) in healthy adults to see if atropine will reach detectable concentrations in plasma following topical oral administration in gel formulation.	Calculate the pharmacokinetic parameter Cmax after topical oral administration of atropine gel	The Cmax will be evaluated at timepoints 0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours after administration of gel to the oral cavity.
Primary	Evaluate pharmacokinetic parameter area under the curve (AUC) in healthy adults to see if atropine will reach detectable concentrations in plasma following topical oral administration in gel formulation.	Calculate the pharmacokinetic parameter AUC after topical oral administration of atropine gel	The AUC will be evaluated at timepoints 0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours after administration of gel to the oral cavity.
Primary	Evaluate pharmacokinetic parameter volume of distribution (Vd) in healthy adults to see if atropine will reach detectable concentrations in plasma following topical oral administration in gel formulation.	Calculate the pharmacokinetic parameter Vd after topical oral administration of atropine gel	The Vd will be evaluated at timepoints 0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours after administration of gel to the oral cavity.
Primary	Evaluate pharmacokinetic parameter clearance (CL) in healthy adults to see if atropine will reach detectable concentrations in plasma following topical oral administration in gel formulation.	Calculate the pharmacokinetic parameter CL after topical oral administration of atropine gel	The CL will be evaluated at timepoints 0, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 8, and 24 hours after administration of gel to the oral cavity.

External Links

•   Prescribing information of Cuvposa-glycopyrrolate liquid.