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Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimer’s disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg/24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated.

Methods

This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n = 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg/24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches.

Results

Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state [AUC0–τ,ss] (97.4; 88.8–106.9), maximum plasma concentration within the dosing interval τ (profile day) at steady state [Cmax,ss] (99.6; 90.4–109.7) and trough plasma concentration at the end of the dosing interval τ (profile day) at steady state [Cτ,ss] (96.8; 86.2–108.9), demonstrated that both patches were bioequivalent. Evaluation of patch adhesion showed better skin adherence for RIV-TDS as well as dermal response scores (skin tolerability after removal).

Conclusions

For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance.

The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28.

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Acknowledgements

The authors would like to thank the SocraTec R&D team: Frank Donath, MD, as deputy of the Principal Investigator, Marina Todorova-Sanjari for protocol writing, coordination and reporting, Steffi Plum and Sabine Ley for coordinating the clinical part as responsible study nurses and Ralph-Steven Wedemeyer, PhD, for pharmacokinetic evaluation. Furthermore, the authors thank Stefan Lösel, PhD, ACC GmbH, Germany for developing the assay, for validation and bioanalytical determination.

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Author notes

  1. Cornelius Koch

    Present address: Luye Pharma Switzerland AG, Basel, Switzerland

Authors and Affiliations

  1. ESTEVE Pharmaceuticals SA, Torre Esteve, Passeig de la Zona Franca, 109, 4ª Planta, 08038, Barcelona, Spain

    Adelaida Morte, Anna Vaqué & Marc Iniesta

  2. SocraTec R&D GmbH, Im Setzling 35, 61440, Oberursel, Germany

    Barbara Schug & Cornelius Koch

  3. Grup de Recerca en Farmacologia Integrada i Neurociencia de Sistemes, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Dr Aiguader 88, Barcelona, Spain

    Rafael De la Torre

  4. Luye Pharma AG, Am Windfeld 35, 83714, Miesbach, Germany

    Bjoern Schurad

Authors
  1. Adelaida Morte
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Corresponding authors

Correspondence to Marc Iniesta or Bjoern Schurad.

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Funding

This study was sponsored by SocraTec R&D GmbH, Esteve Pharmaceuticals is the MAH of this product in Spain and Luye Pharma AG developed and manufactures the product.

Conflict of Interest

Marcos Iniesta, Adelaida Morte and Anna Vaqué are full-time employees of ESTEVE Pharmaceuticals. Cornelius Koch was a full-time employee of SocraTec at the time of the study; currently he is a full-time employee of Luye. Bjoern Schurad is full-time employee of Luye and Barbara Schug is an employee of SocraTec. Rafael De la Torre reports consulting fees for Esteve Pharmaceuticals.

Ethics Approval

Ethics Committee of the Landesärztekammer Thüringen (trial number: 1351riv18ct and date of EC approval: 2018-05-15). Informed consent was obtained from all subjects involved in the study. The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28

Consent to Participate

Written informed consent was obtained from all participants prior to enrolment.

Consent for Publication

Not applicable.

Data Availability

The data presented in this study are available on request to the corresponding author.

Code Availability

Not applicable.

Author Contributions

Marcos Iniesta, Adelaida Morte, Rafael de la Torre and Anna Vaqué reviewed the results and critically discussed, drafted, edited and reviewed all versions of the manuscript and approved the final version. Barbara Schug, Cornelius Koch and Bjoern Schurad conceived or designed the study, contributed to data collection and analysed and interpreted data. All authors have read and agreed to the published version of the manuscript.

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Morte, A., Vaqué, A., Iniesta, M. et al. Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects. Eur J Drug Metab Pharmacokinet 47, 567–578 (2022). https://doi.org/10.1007/s13318-022-00778-5

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  • DOI: https://doi.org/10.1007/s13318-022-00778-5

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