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

Abstract : 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.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03577397
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Soumis le : mercredi 16 février 2022 - 16:37:32
Dernière modification le : mardi 1 mars 2022 - 16:24:41

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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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