Simcyp Limited (a Certara company), Sheffield, UK.
Simcyp Limited (a Certara company), Sheffield, UK.
Eur J Pharm Sci. 2018 Mar 30;115:57-67. doi: 10.1016/j.ejps.2018.01.009. Epub 2018 Jan 5.
There is increasing interest in paediatric drug absorption and the development of biopharmaceutics tools to facilitate the development of oral formulations for neonates, infants and children. We describe the development and application of a physiologically-based model of paediatric drug absorption applicable from full term birth onwards. Paediatric age-specific parameters were included for salivary flow, gastric pH, gastric emptying (and associated food effects) and duodenal bile salt concentrations and the associated algorithms were integrated into a dissolution, absorption and metabolism model as part of a PBPK platform. For other parameters, there was either evidence for no age-related changes or a lack of data, so that adult values were applied. An initial assessment of the model was carried out by simulating the oral absorption of theophylline, paracetamol and ketoconazole over a range of paediatric ages. The absorption of the first two drugs, both BCS class 1 compounds, was predicted to be slower in early neonates compared to older age groups (median t values of 3 vs 2h, respectively), but with invariant fraction absorbed (fa). This is in agreement with clinical observations. The t of ketoconazole, a BCS class 2 compound, was predicted to be about 1h in both neonates and adults, but the fa value was higher in the former (0.87 vs 0.69). There is clearly a need to expand the components of the model as new information on the ontogeny of GI tract parameters becomes available, and to assess it against more in vivo data with evidence of specific age-related changes in oral drug absorption.
人们对儿科药物吸收越来越感兴趣，并开发了生物药剂学工具，以促进为新生儿、婴儿和儿童开发口服制剂。我们描述了一种适用于从足月出生开始的儿科药物吸收生理基础模型的开发和应用。纳入了唾液流量、胃 pH 值、胃排空（和相关食物效应）以及十二指肠胆汁盐浓度的儿科年龄特异性参数，并且相关算法被整合到溶解、吸收和代谢模型中，作为 PBPK 平台的一部分。对于其他参数，要么没有证据表明与年龄相关的变化，要么缺乏数据，因此应用了成人值。通过模拟茶碱、对乙酰氨基酚和酮康唑在一系列儿科年龄范围内的口服吸收，对该模型进行了初步评估。这两种药物（均为 BCS 类 1 化合物）的吸收速度被预测在早期新生儿中比在年龄较大的组中较慢（中位数 t 值分别为 3 小时和 2 小时），但吸收分数（fa）不变。这与临床观察结果一致。酮康唑（BCS 类 2 化合物）的 t 值预计在新生儿和成人中均约为 1 小时，但前者的 fa 值更高（0.87 比 0.69）。随着关于胃肠道参数发育的新信息的出现，显然需要扩展模型的组成部分，并针对具有口服药物吸收特定年龄相关变化证据的更多体内数据对其进行评估。
