Background and Goal of the study
One of the best-adapted options for moderate sedation in pediatric patients is oral midazolam. In many European countries there is currently no oral midazolam licensed product available and off-label use of other forms is common. These forms present very poor acceptability as major drawback.
A new 0.2% (w/v) midazolam solution has been developed, based on the advantages of cyclodextrin inclusion complexes: bitterness masking, solubility and stability improvement.
The present work aimed at evaluating the impact of cyclodextrins on oral midazolam pharmacokinetics (PK) and pharmacodynamics (PD) in adults, in view of the future use of ADV6209 in children. 

Materials and Methods
A Phase I (n=12) randomized study with a standard two-way (15 mg ADV6209 PO - 5 mg Hypnovel® IV) crossover design was performed in order to determine the main PK parameters including absolute oral bioavailability, after single administration of ADV6209.
The sedative effect was measured using a visual analog scale (VAS) for alertness and the observer’s assessment of alertness/sedation (OAA/S) scale at different time points up to 12 hours after administration. Safety and tolerability were also assessed.

Results and Discussion
PK parameters for midazolam (MDZ) and its main active metabolite, α-hydroxymidazolam (-OHM) were determined (see Table - not visible in plain text format)). Oral bioavailability with ADV6209 was 39.4%, in close agreement with literature values for other oral formulations.

Overall, ADV6209 provided sedation (OAA/S score ≤ 17) within 30 minutes and over at least 2 hours and PD scores reflected well the extent of sedation/alertness in relation with midazolam plasma concentrations. The minimum plasma concentration required to reach a sedative effect (Cmin) was 53.05 ng/mL (95 % CI, 46.65, 60.44).
Midazolam complexation with cyclodextrins in order to obtain a solution with improved pharmaceutical characteristics and palatability did not seem to alter PK and PD parameters. Safety and tolerability were also very good.
Conclusion
Results in adults indicated that no significant modifications of PK and PD parameters should be expected in children administered ADV6209 and supported further evaluation of this innovative product for moderate sedation in the paediatric population.

A two-way randomized cross-over pharmacokinetic and pharmacodynamic evaluation of ADV6209, an innovative oral solution of midazolam