Examination of betahistine bioavailability in combination with the monoamine oxidase B inhibitor, selegiline, in humans-a non-randomized, single-sequence, two-period titration, open label single-center phase 1 study (PK-BeST).

Background

Betahistine was registered in Europe in the 1970s and approved in more than 80 countries as a first-line treatment for Menière's disease. It has been administered to more than 150 million patients. However, according to a Cochrane systematic review of betahistine and recent meta-analyses, there is insufficient evidence to say whether betahistine has any effect in the currently approved dosages of up to 48 mg/d. A combination with the monoamine oxidase B (MAO-B) inhibitor, selegiline, may increase the bioavailability of betahistine to levels similar to the well-established combination of L-DOPA with carbidopa or benserazide in the treatment of Parkinson's disease. We investigated the effect of selegiline on betahistine pharmacokinetics and the safety of the combination in humans.

Methods

In an investigator-initiated prospective, non-randomized, single-sequence, two-period titration, open label single-center phase 1 study, 15 healthy volunteers received three single oral dosages of betahistine (24, 48, and 96 mg in this sequence with at least 2 days' washout period) without and with selegiline (5 mg/d with a loading period of 7 days). Betahistine serum concentrations were measured over a period of 240 min at eight time points (area under the curve, AUC0-240 min). This trial is registered with EudraCT (2019-002610-39) and ClinicalTrials.gov.

Findings

In all three single betahistine dosages, selegiline increased the betahistine bioavailability about 80- to 100-fold. For instance, the mean (±SD) of the area under curve for betahistine 48 mg alone was 0.64 (+/-0.47) h

Interpretation

This phase 1 trial shows that the MAO-B inhibitor selegiline increases betahistine bioavailability by a factor of about 80 to 100. No safety concerns were detected. Whether the increased bioavailability has an impact on the preventive treatment of Menière's disease, acute vestibular syndrome, or post-BPPV residual dizziness has to be evaluated in placebo-controlled trials.

Clinical trial registration

https://clinicaltrials.gov/study/NCT05938517?intr=betahistine%20and%20selegiline&rank=1, identifier: NCT05938517.

Informations de copyright

Copyright © 2023 Strupp, Churchill, Naumann, Mansmann, Al Tawil, Golentsova and Goldschagg.

Déclaration de conflit d'intérêts

The study received funding from Cures within Reach, and the Knight family, Chicago, U.S.A. The foundation and the Knight family had no role in the design, management, data collection, analyses, or interpretation of the data or in writing the manuscript or the decision to submit for publication. MS is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology, and Section Editor of F1000, is investor and share-holder of IntraBio; IntraBio is the owner of the patent for the combined use of betahistine and selegiline, he has received speaker's honoraria from Abbott, Auris Medical, Biogen, Eisai, Grünenthal, GSK, Henning Pharma, Interacoustics, J&J, MSD, NeuroUpdate, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris, receives support for clinical studies from Decibel, U.S.A., Cures within Reach, U.S.A. and Heel, Germany, distributes “Mglasses” and “Positional vertigo App”, and acts as a consultant for Abbott, AurisMedical, Bulbitec, Heel, IntraBio, Sensorion and Vertify. GC is a founding scientist and consultant for IntraBio. NG acts as a reviewer for IntraBio and as Review Editor on the Editorial Board of Neuro-Otology (specialty section of Frontiers in Neurology). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.