对于儿科PBPK建模的脏输送器本体基因概况的最大概率估计
J Porter Hunt1, Samuel Dubinsky2, Autumn M McKnite1
1University of Utah, Salt Lake City, Utah, USA.
CPT: pharmacometrics & systems pharmacology
|December 29, 2023
概括
儿科生理学基础的药理动力学 (PBPK) 模型现在包括脏输送器 (RT) 机体生成概况. 这些新型概况改善了对新生儿和婴儿药物处置的预测,使得儿科剂量优化成为可能.
科学领域:
- 药理学 药理学是指药理学的学科.
- 儿科药物开发 儿科药物开发
- 脏生理学 脏生理学
背景情况:
- 婴儿的最佳药物剂量需要了解运输体 (RT) 活性,这种活性随着成熟而变化.
- 儿科生理学基础的药理动力学 (PBPK) 模型需要准确的RT发育特征,特别是对于新生儿来说,以预测药物处置.
研究的目的:
- 在儿科患者群体中开发和验证关键运输体的新型本体生殖特征.
- 提高儿科PBPK模型的准确性,以预测婴儿和新生儿的药物药理动力学.
主要方法:
- 来自人类脏样本的RT表达数据被用来通过最大概率估计来估计本体生成概况.
- 评估了四种RT基质 (乙克洛维尔,西普罗素,富洛塞米德,美罗) 的PBPK模型,并评估了具有或没有新型本体生成概况的PBPK模型.
- 模型性能使用平均折叠误差 (AFE),绝对平均折叠误差 (AAFE) 和在5-95%的预测区间内的观测比例进行评估.
主要成果:
- 估计了OAT1,OAT3,OCT2,P-gp,URAT1,BCRP,MATE1,MRP2,MRP4和MATE-2 K. 的新最大概率概况.
- 包括OAT3,P-gp和MATE1本体基因概况显著提高了婴儿罗塞米德和新生儿美洛的PBPK模型准确性.
- 新生儿西普罗洛克萨辛模拟的模型性能得到了改善,预测间隔5-95%内的数据百分比从48%增加到98%.
结论:
- 新的RT本体基因配置文件大大提高了新生儿PBPK模型的性能.
- 这些对RT活性成熟期差异的验证估计对于优化儿科患者药物剂量至关重要.
- 开发的配置文件为婴儿和儿童的精确药物治疗提供了宝贵的工具.
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