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Article Dans Une Revue European Journal of Pharmaceutical Sciences Année : 2018

Population pharmacokinetic evaluation of ADV6209, an innovative oral solution of midazolam containing cyclodextrin

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Résumé

Introduction: In the absence of a licensed formulation in many countries worldwide, ADV6209, an innovative 2 mg/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 alpha-hydroxymidazolam. Results: The body weight covariate was found to have a significant impact on midazolam and alpha-hydroxymidazolam clearance, and on midazolam volume of distribution. The population pharmacokinetic model indicated that 77% of the midazolam dose was absorbed within 30 min after oral administration. Parameter estimations for a subject of 34 kg indicated values of midazolam clearance of 34.7 l.h(-1), a central volume of distribution of 27.9 l and a peripheral volume of distribution of 413 l. 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 alpha-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.

Dates et versions

hal-03577397 , version 1 (16-02-2022)

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Frederic Marcon, Catherine Guittet, Maria A. Manso, Ingrid Burton, Luc-Andre Granier, et al.. Population pharmacokinetic evaluation of ADV6209, an innovative oral solution of midazolam containing cyclodextrin. European Journal of Pharmaceutical Sciences, 2018, 114, pp.46-54. ⟨10.1016/j.ejps.2017.11.030⟩. ⟨hal-03577397⟩
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