A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Innovative Oral Solution of Midazolam (ADV6209).

PURPOSE: The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing γ-cyclodextrins (ADV6209).

METHODS: A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel®, Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite α-hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability.

RESULTS: Caucasian healthy subjects (n = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 ± 15.5 min after oral administration for a duration of 48.5 ± 35.4 min. Double peak phenomenon was observed in 5 patients.

CONCLUSIONS: Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.