A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety

Abstract

Midazolam is one of many bitter drugs where provision of a suitable oral paediatric formulation, particularly in the pre-anaesthetic setting, remains a challenge. To overcome this problem, a novel chocolate-based tablet formulation has been developed with positive pre-clinical results. To further investigate the potential of this formulation, 150 children aged 3-16 years who were prescribed midazolam as a premedication were randomly assigned to receive 0.5 mg.kg either as the novel formulation or an intravenous solution given orally, which is the current standard at our institution. Tolerability was assessed by each child, parent and nurse using a 5-point facial hedonic scale and efficacy was determined as the time to onset of sedation. Blood samples for midazolam and 1-hydroxymidazolam levels were analysed using high-performance liquid chromatography. Population pharmacokinetics were evaluated using non-linear mixed effects modelling. The novel formulation had significantly improved tolerability scores from children, parents and nurses (all p < 0.001). Time to effect was not different between the groups (p = 0.140). The pharmacokinetics of midazolam and 1-hydroxymidazolam were able to be modelled simultaneously. The novel formulation was subject to a higher estimated first-pass metabolism compared with the intravenous solution (8.6% vs. 5.0%) and a significantly lower relative bioavailability of 82.1% (p = 0.013), with no other significant differences. Exposure relative to dose was in the range previously reported for midazolam syrup. We conclude that the novel chocolate-based formulation of midazolam provides improved tolerability while remaining efficacious with suitable pharmacokinetics when used as a premedicant for children.

The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study

“…This finding highlights the importance of knowledge on disposition of the metabolites of midazolam. The metabolism and disposition of midazolam and the primary metabolite OHM after oral dosing have been described in preterm neonates and older children, 10,13,14,26,27 but gaps remain for term neonates to children < 1 year old. Most importantly, to the best of our knowledge, data on systemic exposure of OHMG in adults and children after oral dosing are not available.…”

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

“…The off-label administration of intravenous drug formulations orally is another situation where the treatment options for pediatric patients is not optimal and a need for dosage form development is obvious. The administration of intravenous formulations orally is common practice in other countries as well [16,31]. In Australia, chewable chocolate-tasting tablets containing midazolam showed better acceptability compared to the commonly used intravenous formulation in a randomized trial involving children receiving premedication before anesthesia [31].…”

“…The administration of intravenous formulations orally is common practice in other countries as well [16,31]. In Australia, chewable chocolate-tasting tablets containing midazolam showed better acceptability compared to the commonly used intravenous formulation in a randomized trial involving children receiving premedication before anesthesia [31]. Available formulations and prevailing practices may differ among hospitals and countries.…”

Premedication in children: does taste matter?

“…In this issue of Anaesthesia, Salman et al. report on their development of a novel, chocolate‐flavoured oral preparation of midazolam. They included 150 patients aged between 3 and 16 years who had been prescribed oral midazolam in a dose of 0.5 mg.kg −1 .…”