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).
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.
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.
Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.
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- λ z :
Terminal elimination rate constant
- AUC 0 → ∞ :
Area under the concentration-time curve from zero up to infinity with extrapolation of the terminal phase
- AUC 0 → Tlast :
Area under the concentration-time curve from 0 up to the last time point
- C max :
Observed maximum plasma concentration after administration
- D :
- EC50 :
Plasma concentration at which the predicted probability of a positive response is 50%
Limit of quantification
- F :
- MR :
Observer’s assessment of alertness/sedation scale
- R2 :
Coefficient of determination
- T 1/2 :
- T max :
Time to reach C max
Visual analogue scale
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ACKNOWLEDGEMENTS AND DISCLOSURES
Advicenne Pharma financed this study. Dr. Fauchoux provided and cared for study subjects and collected data and Dr. Patat provided scientific advice for study conduct.
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Guittet, C., Manso, M., Burton, I. et al. A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Innovative Oral Solution of Midazolam (ADV6209). Pharm Res 34, 1840–1848 (2017). https://doi.org/10.1007/s11095-017-2193-4
- Conscious sedation