基于人群生理学的药理动力学建模以确定本体性:儿童罕见疾病中的定量临床药理学示例
Yumi Cleary1,2, Bhagwat Prasad3, Kayode Ogungbenro1
1Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK.
CPT: pharmacometrics & systems pharmacology
|January 29, 2026
概括
基于人群生理学上的药理动力学 (PBPK) 建模估计了儿童的药物代谢酶和输送体本体. 这种方法提高了儿科PBPK模型的资格,并支持基于模型的药物开发.
科学领域:
- 药理学和药物开发领域
- 儿科临床药理学 儿童临床药理学
- 计算生物学 计算生物学
背景情况:
- 基于生理学上的药理动力学 (PBPK) 模型对于儿科药物剂量和临床药理学至关重要,但由于数据不确定性,其监管接受度有限.
- 对药物代谢酶 (DME) 和转运体的不准确的本体生成数据显著阻碍了准确的儿科药物动力学 (PK) 预测和PBPK模型资格.
- 伦理约束限制了儿科临床药理学研究,越来越依赖预测模型.
研究的目的:
- 提出和说明一个人口PBPK建模策略,以增强儿科PK外推.
- 在儿科PBPK建模中解决对DME和传送器的模两可的本体生成数据所带来的挑战.
- 促进儿童群体的基于模型的药物开发 (MIDD).
主要方法:
- 采用了一个群体PBPK建模方法,类似于全身PBPK.
- 使用非线性混合效应建模,从稀疏的儿科和成人PK数据中估计DME/载体本体基因.
- 该策略以使用risdiplam用于脊柱肌肉缩治疗为例.
主要成果:
- 种群PBPK建模可以估计DME/传送器本体生成函数.
- 这种方法可以更好地将PK预测推断到未经研究的儿科群体.
- 该方法有助于PK提取和药物相互作用 (DDI) 风险评估.
结论:
- 人口PBPK建模提供了一个强大的策略,以克服儿科PBPK中的本体基因数据不一致性.
- 这种方法提高了PBPK模型对儿童定量临床药理学的资格.
- 它加速了最佳儿科剂量的发现,并指导了适当的药物使用,特别是在罕见的儿科疾病中.
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