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Comparison of the Systemic and Local Pharmacokinetics of Clonidine Mucoadhesive Buccal Tablets with Reference Clonidine Oral Tablets in Healthy Volunteers: An Open-Label Randomised Cross-Over Trial

Abstract

Introduction

The clonidine mucoadhesive buccal tablet (MBT) is a novel delivery system resulting in high and sustained concentrations of clonidine in the oral cavity. In a phase II clinical trial, clonidine MBT reduced the incidence of severe oral mucositis (OM) compared to placebo in head and neck cancer patients undergoing chemoradiation. This study compared the pharmacokinetics (PK), safety and tolerability of clonidine MBT with a reference oral tablet (OT).

Methods

This was a randomised, three-period, single-dose crossover study in 36 healthy subjects aged 18–50 years. Eligibility was assessed within 14 days of the first dose. IMP was administered in the fasted state on day 1 of each treatment period. PK samples were collected up to 24 h (saliva)/96 h (blood) for measurement of the clonidine concentration. Safety and tolerability were evaluated at specified times throughout the study. A washout period of at least 7 days was observed between administrations.

Results

Clonidine MBT (50 and 100 µg) applied to the upper gum resulted in a dose-proportional increase in saliva (C max and AUC0–t ) and plasma (Cmax and AUC0–inf) clonidine levels. Clonidine MBT was considered to mimic a continuous release of clonidine in plasma, significantly decreasing the C max and AUC and increasing the T max when compared with the reference clonidine HCl tablets. Clonidine MBT exhibited high and prolonged concentrations in saliva where concentrations with the clonidine HCl tablet were negligible. Clonidine MBT exhibited a favourable safety profile with significantly fewer subjects reporting AEs (dry mouth and fatigue) and a reduction in blood pressure when compared to the reference clonidine HCl tablets.

Conclusion

Clonidine MBT is well tolerated and exhibits proportional saliva and plasma PK over the 50–100-µg dose level. The MBT results in higher saliva concentrations and lower systemic exposure than OT, which was associated with a trend towards fewer adverse events and less dry mouth, fatigue and hypotensive effect.

Funding

Onxeo SA.

Trial Registration

ClinicalTrials.gov identifier, NCT02548806.

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Acknowledgements

Sponsorship for this study and article processing charges was funded by Onxeo SA (France) and conducted at Simbec Research, Ltd., a commercial phase I unit in the UK. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. The authors would like to thank all volunteers involved in the study and all participating site staff. This work was also presented, in part, at the 2016 European Society for Medical Oncology conference (Copenhagen, Denmark). The authors would also like to thank Dr Nadine Aawar for her review and proof reading of the manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

Disclosures

Bérangère Vasseur was an employee of Onxeo SA at the time of this publication and had stock options in the company. Laetitia Houdas was an employee of Onxeo SA at the time of this publication and had stock options in the company. Neslihan Yesiltas Emul was an employee of Onxeo SA at the time of this publication and had stock options in the company. Alain Dufour has provided paid pharmacokinetic consultancy to Onxeo SA in relation to this project. At the time of publication Helen Goodwin was an employee of Simbec Research, a contract research organisation paid by Onxeo SA to design, conduct, analyse and report this clinical trial. At the time of publication Kathryn Harries was an employee of Simbec Research, a contract research organisation paid by Onxeo SA to design, conduct, analyse and report this clinical trial. At the time of publication Simon Hutchings was an employee of Simbec Research, a contract research organisation paid by Onxeo SA to design, conduct, analyse and report this clinical trial.

Compliance with Ethics Guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all participants for being included in the study.

Data Availability

The data sets analysed during the current study are available from the corresponding author on reasonable request.

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Correspondence to Simon Hutchings.

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Vasseur, B., Dufour, A., Houdas, L. et al. Comparison of the Systemic and Local Pharmacokinetics of Clonidine Mucoadhesive Buccal Tablets with Reference Clonidine Oral Tablets in Healthy Volunteers: An Open-Label Randomised Cross-Over Trial. Adv Ther 34, 2022–2032 (2017). https://doi.org/10.1007/s12325-017-0585-9

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Keywords

  • Clonidine pharmacokinetics
  • Head and neck cancer
  • Mucoadhesive buccal tablet
  • Oncology
  • Oral mucositis