A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Innovative Oral Solution of Midazolam (ADV6209)

Abstract

Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.

Midazolam oral solution (Ozalin®): a profile of its use for procedural sedation or premedication before anaesthesia in children

“…Oral formulations of midazolam, including Ozalin, have a rapid onset and short duration of action [1,21,22]. For example, in a study in 12 healthy adults [22], a sedative effect was observed ≈ 30 min after administration of a single dose of Ozalin 5 mg and lasted for ≈ 50 min. Maximum mean sedation levels occured 0.5-1 h post-administration, with complete alertness in all individuals at 4 h post-administration [22].…”

“…α-hydroxymidazolam) [23]. The model incorporated data from single-dose studies of midazolam in a total of 49 participants, including 12 healthy adults [22] and 37 paediatric patients (5 infants aged 0.5-2 years, 10 children aged 0.5-11 years and 12 adolescents aged 12-17 years) [23]. Overall, the pharmacokinetic values with Ozalin were close to those reported for extemporaneous oral midazolam solutions/syrups in previous studies in paediatric patients [24,25].…”

“…• Rapid absorption Following oral administration of a dose of Ozalin, 77% of midazolam was absorbed within 30 min [23], therefore, Ozalin should be given to paediatric patients ≈ 30 min before the procedure/anaesthesia (Table 1) [1]. A second apparent midazolam peak may occur in some patients and are thought to be caused by delayed gastric emptying [22,23]. • Age-dependent metabolism Midazolam undergoes first-pass metabolism by cytochrome P450 (CYP) 3A4 enzymes to the pharmacologically active primary metabolite α-hydroxymidazolam, which account for 30-50% of the clinical effects of midazolam [1].…”

“…The inclusion of γ-cyclodextrins in the Ozalin formulation of midazolam had little effect on the pharmacokinetic properties of midazolam, as shown by the results of single-dose studies in healthy adults [22,26] and adolescent patients [23].…”

“…In healthy adults, Ozalin had a relative bioavailability of 39.6% and a slightly shorter terminal half-life (t ½ ) than intravenous midazolam (Table 2) [22]. The pharmacokinetic profile of Ozalin in adults was similar to that of the same dose of an extemporaneously prepared oral midazolam solution (Table 2), with a relative bioavailability of 97.4% (absolute bioavailability ≈ 53% for both formulations) [26].…”