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

S. Salman, E. K.Y. Tang, L. C. Cheung, M. N. Nguyen, D. Sommerfield, L. Slevin, L. Y. Lim, B. S. von Ungern Sternberg

Research output: Contribution to journalArticle

1 Citation (Scopus)

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-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.

Original languageEnglish
Pages (from-to)1469-1477
Number of pages9
JournalAnaesthesia
Volume73
Issue number12
Early online date9 Jul 2018
DOIs
Publication statusPublished - Dec 2018

Fingerprint

Midazolam
Pharmacokinetics
Pediatrics
Safety
Nurses
Pleasure
Premedication
Biological Availability
Tablets
Anesthetics
Parents
High Pressure Liquid Chromatography
Pharmaceutical Preparations
Population

Cite this

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title = "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-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.",
keywords = "Midazolam, Paediatrics oral dosage, Pre-operative anxiety",
author = "S. Salman and Tang, {E. K.Y.} and Cheung, {L. C.} and Nguyen, {M. N.} and D. Sommerfield and L. Slevin and Lim, {L. Y.} and {von Ungern Sternberg}, {B. S.}",
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A novel, palatable paediatric oral formulation of midazolam : Pharmacokinetics, tolerability, efficacy and safety. / Salman, S.; Tang, E. K.Y.; Cheung, L. C.; Nguyen, M. N.; Sommerfield, D.; Slevin, L.; Lim, L. Y.; von Ungern Sternberg, B. S.

In: Anaesthesia, Vol. 73, No. 12, 12.2018, p. 1469-1477.

Research output: Contribution to journalArticle

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T2 - Pharmacokinetics, tolerability, efficacy and safety

AU - Salman, S.

AU - Tang, E. K.Y.

AU - Cheung, L. C.

AU - Nguyen, M. N.

AU - Sommerfield, D.

AU - Slevin, L.

AU - Lim, L. Y.

AU - von Ungern Sternberg, B. S.

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N2 - 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.

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