Population pharmacokinetic evaluation of ADV6209, an innovative oral solution of midazolam containing cyclodextrin
Frédéric Marçon, Catherine Guittet, Maria A Manso, Ingrid Burton, Luc-André Granier, Philippe Jacqmin, Hervé Dupont, Frédéric Marçon, Catherine Guittet, Maria A Manso, Ingrid Burton, Luc-André Granier, Philippe Jacqmin, Hervé Dupont
Abstract
Introduction: In the absence of a licensed formulation in many countries worldwide, ADV6209, an innovative 2mg/ml oral solution of midazolam containing cyclodextrin, has been developed for moderate sedation in paediatric patients. Population pharmacokinetics for ADV6209 is reported.
Methods: Plasma concentration data were collected from 37 paediatric patients and 12 healthy adults recruited in a single dose, open-label phase II pharmacokinetic study and in a single dose, randomised, open-label two-period crossover bioavailability study, respectively. Data were analysed using non-linear mixed effect modelling. Plasma concentrations of midazolam were described by a two-compartment model. An additional one-compartment model was added for α- hydroxymidazolam.
Results: The body weight covariate was found to have a significant impact on midazolam and α-hydroxymidazolam clearance, and on midazolam volume of distribution. The population pharmacokinetic model indicated that 77% of the midazolam dose was absorbed within 30min after oral administration. Parameter estimations for a subject of 34kg indicated values of midazolam clearance of 34.7l·h-1, a central volume of distribution of 27.9l and a peripheral volume of distribution of 413l. A higher metabolic ratio and a higher midazolam clearance per body weight were observed in the youngest group of subjects, in accordance with literature data. The clearance per body weight of α-hydroxymidazolam remained constant over the different age groups.
Conclusion: Pharmacokinetic parameters were close to those reported in the literature with midazolam extemporaneous oral solutions or syrups, demonstrating that cyclodextrin had no significant effect on measured parameters.
Keywords: Child; Cyclodextrins; Gamma-Cyclodextrin (PubChem CID: 5287407); Midazolam; Midazolam (PubChem CID: 4192); Moderate sedation; Pharmacokinetics.
Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Source: PubMed