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

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 (AUC(96-264), Cmax(96-264) and Cmin(96-264)) 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. Trial Registration Number: Protocols are registered in ClinicalTrials.gov: NCT03659435 and EudraCT: 2018-001570-18.