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).
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.
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:
|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)|
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
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.