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Comparison of the systemic and local pharmacokinetics, safety and tolerability of clonidine mucoadhesive buccal tablets with reference clonidine oral tablets in healthy volunteers

Date

09 Oct 2016

Session

Poster display

Presenters

Béatrice Petre-Lazar1

Citation

Annals of Oncology (2016) 27 (6): 497-521. 10.1093/annonc/mdw390

Authors

B. Petre-Lazar11, G. Sharma2, S. Hutchings3, H. Goodwin4, N. Yesiltas Emul5, G. Dixon1, B. Vasseur1

Author affiliations

  • 1 Clinical Department, Onxeo, 75015 - Paris/FR
  • 2 Clinical Pharmacology, Simbec Research Ltd, Merthyr Tydfil/GB
  • 3 Scientific & Regulatory Affairs, Simbec Research Ltd, Merthyr Tydfil/GB
  • 4 Biometrics, Simbec Research Ltd, Merthyr Tydfil/GB
  • 5 Pharmaceutical Department, Onxeo, 75015 - Paris/FR
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Resources

Background

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 2 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 randomized, 3 period single dose crossover study in 36 healthy subjects aged 18-50 yr. Eligibility was assessed within 14 d 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 clonidine concentration. Safety and tolerability were evaluated at specified times throughout the study. A washout period of at least 7 d was observed between administrations.

Results

There were 13 and 15 adverse events (AEs) considered at least possibly related to IMP following 50 µg and 100 µg MBT, respectively, compared to 26 following 100 µg clonidine OT. All AEs were either mild or moderate in severity. No Serious AEs were reported. Dry mouth and fatigue were reduced in clonidine MBT 50 µg and 100 µg versus clonidine OT respectively 28-29% vs 71% for dry mouth and 0% vs 23% for fatigue. Peak mean reductions in systolic/diastolic blood pressure were 5.7/3.7 and 7.1/4.2 mmHg for clonidine MBT 50 µg and 100 µg, respectively, compared with 13.4/7.8 mmHg for clonidine OT. Mean (SD) maximum saliva and plasma concentration and exposure data is presented below:

PLASMA PLASMA SALIVA PLASMA
Cmax (pg/mL) AUC0-t (h*pg/mL) Cmax (pg/mL) AUC0-t (h*pg/mL)
100 µg clonidine OT 399 (86.1) 5640 (1390) 2630 (2140) 14600 (6820)
100 µg clonidine MBT 222 (59.3) 4790 (1220) 387000 (148000) 2920000 (1730000)
50 µg clonidine MBT 104 (29.6) 1660 (720) 209000 (132000) 1440000 (890000)

Conclusions

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, less dry mouth, fatigue and hypotensive effect.

Clinical trial identification

EudraCT NUMBER: 2015-001836-40 Protocol v2 dated 29 June 2015

Legal entity responsible for the study

Study sponsor/legal entity: Onxeo Study Contract Research Organisation responsible for coordination and running of the study: Simbec Research Dtd

Funding

Onxeo

Disclosure

B. Petre-Lazar1, N. Yesiltas Emul, G. Dixon, B. Vasseur: Corporate-sponsored research. G. Sharma, S. Hutchings, H. Goodwin: Simbec Research Ltd is a commercial Contract Research Organisation contracted by Onxeo to perform this Phase I clinical study.

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