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)

Strupp, Michael; Churchill, Grant C.; Naumann, Ivonne; Mansmann, Ulrich; Al Tawil, Amani; Golentsova, Anastasia; Goldschagg, Nicolina (2023): 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). Frontiers in Neurology, 14: 1271640. ISSN 1664-2295

Abstract

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 * ng/mL and for betahistine plus selegiline 53.28 (+/-37.49) h * ng/mL. The half-life time of around 30 min was largely unaffected, except for the 24 mg betahistine dosage. In total, 14 mild adverse events were documented.

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.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892