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

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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 :

Dose administered

EC50 :

Plasma concentration at which the predicted probability of a positive response is 50%




Limit of quantification

F :

Absolute bioavailability

MR :

Metabolic ratio


Observer’s assessment of alertness/sedation scale

R2 :

Coefficient of determination

T 1/2 :

Terminal half-life

T max :

Time to reach C max


Visual analogue scale


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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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Correspondence to Frédéric Marçon.

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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).

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Key Words

  • Benzodiazepines
  • Bioavailability
  • Conscious sedation
  • Cyclodextrins
  • Midazolam