Frédéric Marçon1, Catherine Guittet2, Maria A Manso2, Ingrid Burton3, Luc-André Granier2, Philippe Jacqmin4, Hervé Dupont5. 1. Groupe de Recherche En Pharmacotechnie Pédiatrique, Pharmacie à Usage Intérieur, CHU Amiens-Picardie, Amiens, France; CNRS UMR 7378, Amiens, France. Electronic address: Marcon.frederic@chu-amiens.fr. 2. Advicenne, Nîmes, France. 3. ClinBay SPRL, Genappe, Belgium. 4. MnS SPRL, Dinant, Belgium. 5. Pôle Anesthésie-Réanimation, CHU Amiens-Picardie, Amiens, France; INSERM U1088, Amiens, France.
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.
RCT Entities:
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.
Authors: Carmen Flores-Pérez; Luis Alfonso Moreno-Rocha; Juan Luis Chávez-Pacheco; Norma Angélica Noguez-Méndez; Janett Flores-Pérez; María Fernanda Alcántara-Morales; Luz Cortés-Vásquez; Lina Sarmiento-Argüello Journal: Saudi Pharm J Date: 2022-05-23 Impact factor: 4.562