Generic placeholder image

Current Alzheimer Research

Author(s): Bjoern Schurad, Cornelius Koch, Barbara Schug, Adelaida Morte, Anna Vaqué, Rafael De la Torre and Marc Iniesta*

DOI: 10.2174/1567205019666220823105059

DownloadDownload PDF Flyer Cite As
Comparative Bioavailability Study of a Novel Multi-Day Patch Formulation of Rivastigmine (Twice Weekly) with Exelon® Transdermal Patch (Daily)- A Randomized Clinical Trial

Page: [541 - 553] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer’s dementia, is administered once daily transdermal patches, enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation was developed with greater convenience for patients’ therapeutic management.

Objective: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once-daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h.

Design: Single-center, open-label, randomized, multiple-dose study in healthy male adults in a 2- period, 2-sequence-crossover design with multiple applications.

Methods: Patches were applied on 11 consecutive days for Exelon® and a 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated.

Results: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00-125.00%. They were 113.64% (107.33-120.33), 105.14% (98.38- 112.38) and 107.82% (97.78-118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®.

Conclusion: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once daily in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.

Keywords: Alzheimer disease, rivastigmine, transdermal patch, bioavailability, bioequivalence, healthy subjects, butyryl cholinesterase, pharmacokinetics, adhesion  

[1]
Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer’s disease: An update. J Cent Nerv Syst Dis 2020; 12.
[http://dx.doi.org/10.1177/1179573520907397] [PMID: 32165850]
[2]
García-Morales V, González-Acedo A, Melguizo-Rodríguez L, et al. Current understanding of the physiopathology, diagnosis and therapeutic approach to Alzheimer’s disease. Biomedicines 2021; 9(12): 1910.
[3]
Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018; 141(7): 1917-33.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[4]
Kaestli LZ, Wasilewski-Rasca AF, Bonnabry P, Vogt-Ferrier N. Use of transdermal drug formulations in the elderly. Drugs Aging 2008; 25(4): 269-80.
[http://dx.doi.org/10.2165/00002512-200825040-00001] [PMID: 18361538]
[5]
Yunusa I, Alsahali S, Rane A, Eguale T. Comparative value of cholinesterase inhibitors and memantine in persons with moderate-to-severe Alzheimer’s disease in the united states: A cost-effectiveness analysis. J Alzheimers Dis Rep 2021; 5(1): 705-13.
[http://dx.doi.org/10.3233/ADR-210307] [PMID: 34755044]
[6]
Khoury R, Rajamanickam J, Grossberg GT. An update on the safety of current therapies for Alzheimer’s disease: Focus on rivastigmine. Ther Adv Drug Saf 2018; 9(3): 171-8.
[http://dx.doi.org/10.1177/2042098617750555] [PMID: 29492246]
[7]
Exelon Procedure No: EMEA/H/C/169/X/38 Scientific Discussion 2007. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion-variation/exelon-h-c-169-x-0038-epar-scientific-discussion-extension_en.pdf
[8]
Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy 2000; 20(1): 1-12.
[http://dx.doi.org/10.1592/phco.20.1.1.34664]
[9]
Bhatt J, Subbaiah G, Kambli S, et al. A rapid and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the estimation of rivastigmine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852(1-2): 115-21.
[http://dx.doi.org/10.1016/j.jchromb.2007.01.003] [PMID: 17296337]
[10]
Frankfort SV, Ouwehand M. Maria J van Maanen, Hilde Rosing, Linda R Tulner, Jos H Beijnen. A simple and sensitive assay for the quantitative analysis of rivastigmine and its metabolite NAP 226-90 in human EDTA plasma using coupled liquid chromatography and tandem mass spectrometry. Rapid Commun Mass Spectrom 2006; 20(22): 3330-6.
[http://dx.doi.org/10.1002/rcm.2737] [PMID: 17044120]
[11]
Pommier F, Frigola R. Quantitative determination of rivastigmine and its major metabolite in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 784(2): 301-13.
[http://dx.doi.org/10.1016/S1570-0232(02)00816-4] [PMID: 12505778]
[12]
EMA: Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms, EMA/CHMP/EWP/280/96 Rev1 2014. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf
[13]
Ellman GL, Courtney KD, Andres V Jr, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2): 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[14]
FDA: Bioanalytical Method Validation Guidance for Industry. May 2018. Available from: https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf
[15]
EMEA: Guideline on bioanalytical method validation. MEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2*21 July 2011. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_ en.pdf
[16]
Lefèvre G. Sędek G, Jhee SS, et al. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer’s disease patients. Clin Pharmacol Ther 2008; 83(1): 106-14.
[http://dx.doi.org/10.1038/sj.clpt.6100242] [PMID: 17522596]
[17]
EMA: Guideline on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **. 2010. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf?
[18]
Lefèvre G. Sędek G, Huang HLA, et al. Pharmacokinetics of a rivastigmine transdermal patch formulation in healthy volunteers: Relative effects of body site application. J Clin Pharmacol 2007; 47(4): 471-8.
[http://dx.doi.org/10.1177/0091270006297748] [PMID: 17389556]
[19]
Exxelon F. Exxelon, fachinformation Exelon® transdermales Pflaster. Novartis Pharma. 2018. Available from: https://www.novartis.de/arzneimittel-produkte/exelon-pflaster-informationen-zur-risikominimierung
[20]
Clinical Study Report – final, 2019-09-12 – 1352riv18ct. EudraCTNo.: 2018-001570-18. Open, randomized, 2-period, 2-sequence, cross-over relative bioavailability study to investigate the pharmacokinetics and to assess the bioequivalence of a rivastigmine test patch formulation 9.5 mg/24 h (twice weekly patch) compared to the reference Exelon® 9.5 mg/24 h (once daily patch) applied for 11 days.
[21]
Clinical Study Report – final, 2015-04-20– 1293riv14ct. EudraCTNo.: 2014-001201-40. Open, randomized, 2-period, 2-sequence, cross-over proof-of concept study to investigate relative bioavailability and pharmacodynamic effect of a test transdermal patch formulation of rivastigmine compared with Exelon® transdermal patch with a release rate of 4.6 mg/24 h in healthy subjects.