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

• Published in: Anaesthesia Vol. 73; no. 12; pp. 1469 - 1477
• Main Authors: Salman, S., Tang, E. K. Y., Cheung, L. C., Nguyen, M. N., Sommerfield, D., Slevin, L., Lim, L. Y., Ungern Sternberg, B. S.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.12.2018
• Subjects: Administration, Oral; Anxiety; Bioavailability; Biotransformation; Child; Child, Preschool; Children; Chocolate; Drug Compounding; Effectiveness; Female; Humans; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - pharmacokinetics; Infant; Intravenous administration; Liquid chromatography; Male; Medical personnel; Metabolism; Midazolam; Midazolam - adverse effects; Midazolam - analogs & derivatives; Midazolam - pharmacokinetics; Nurses; paediatrics oral dosage; Parents; Patient Safety; Pediatrics; Pharmacokinetics; Pharmacology; Preanesthetic Medication; pre‐operative anxiety; Prospective Studies; Single-Blind Method; Syrup; Syrups; Taste; midazolam; paediatrics oral dosage; pre-operative anxiety
• DOI: 10.1111/anae.14318
• ISSN: 0003-2409; 1365-2044

Summary 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−1 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.