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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.

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Authors and Affiliations

  1. Advicenne Pharma, Nîmes, France

    Catherine Guittet, Maria Manso & Luc-André Granier

  2. ClinBay, Baisy-Thy, Belgium

    Ingrid Burton

  3. Groupe de recherche en pharmacotechnie pédiatrique, Pharmacie à Usage Intérieur, Centre Hospitalier Universitaire d’Amiens, Amiens, France

    Frédéric Marçon

Authors
  1. Catherine Guittet
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  2. Maria Manso
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  3. Ingrid Burton
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  4. Luc-André Granier
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  5. Frédéric Marçon
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Corresponding author

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

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