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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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Abstract

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.

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Abbreviations

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%

iv:

Intravenous

LOQ:

Limit of quantification

F :

Absolute bioavailability

MR :

Metabolic ratio

OAAS:

Observer’s assessment of alertness/sedation scale

R2 :

Coefficient of determination

T 1/2 :

Terminal half-life

T max :

Time to reach C max

VAS:

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.

Author information

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). https://doi.org/10.1007/s11095-017-2193-4

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Key Words

  • Benzodiazepines
  • Bioavailability
  • Conscious sedation
  • Cyclodextrins
  • Midazolam