Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia.
Division of Pharmacy, Faculty of Health and Medical Sciences, School of Allied Health, University of Western Australia, Perth, Australia.
Anaesthesia. 2018 Dec;73(12):1469-1477. doi: 10.1111/anae.14318. Epub 2018 Jul 9.
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.
咪达唑仑是许多苦味药物之一，在预麻醉环境中，特别是提供合适的儿科口服制剂仍然是一个挑战。为了解决这个问题，已经开发了一种新型巧克力片剂型，具有积极的临床前结果。为了进一步研究这种配方的潜力，我们将 150 名年龄在 3-16 岁之间的儿童随机分配，给予 0.5mg/kg 咪达唑仑，一种是新型配方，另一种是我们机构目前的标准，即静脉内溶液口服。通过儿童、家长和护士使用 5 分面部愉悦量表评估耐受性，通过镇静起效时间确定疗效。使用高效液相色谱法分析咪达唑仑和 1-羟基咪达唑仑的血药浓度。使用非线性混合效应模型进行群体药代动力学评估。新型配方在儿童、家长和护士方面的耐受性评分均显著提高（均 p < 0.001）。两组之间的起效时间无差异（p = 0.140）。咪达唑仑和 1-羟基咪达唑仑的药代动力学可以同时建模。与静脉内溶液相比，新型配方的首过代谢估计更高（8.6%比 5.0%），相对生物利用度显著降低 82.1%（p = 0.013），其他无显著差异。与剂量相比，暴露量在咪达唑仑糖浆的先前报道范围内。我们得出结论，新型巧克力基咪达唑仑配方在提供改善的耐受性的同时，仍然有效，药代动力学合适，可作为儿童的预用药。
