一个基于生理学的药理动力学模型,用于预测多克索鲁比辛在多个组织水平的处置,以及定量毒性评估
Fang-Ching Chao1, Eloísa Berbel Manaia1, Gilles Ponchel1
1CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay 91400, France.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
|October 12, 2023
概括
基于生理学上的药理动力学 (PBPK) 建模量化评估了多克索鲁比化疗在细胞水平上的毒性. 这些发现支持当前的剂量方案,并建议输液策略以减轻不良影响.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 计算生物学 计算生物学
背景情况:
- 多克索鲁比是一种重要的化疗药物,但其临床使用受到显著毒性的限制.
- 评估多克索鲁比的细胞毒性对于优化治疗和尽量减少不良影响至关重要.
研究的目的:
- 开发和验证一种基于生理学的药理动力学 (PBPK) 模型,用于定量评估多克索鲁比的细胞毒性.
- 评估不同的多克索鲁比剂量方案和输液策略,以减轻风险.
主要方法:
- 开发了一种经过修改的PBPK模型结构,结合多个物种的推断来预测多克索鲁比辛在各种组织中的处置.
- 用临床组织数据和细胞内多克索鲁比辛度来验证模型的性能.
- 通过定义毒性水平和计算不同剂量场景的曲线下的面积 (AUC) 来评估细胞毒性.
主要成果:
- 该PBPK模型准确地预测了多种组织中的多克索鲁比辛排放,实现了2.12的整体绝对平均折叠误差 (AAFE).
- 通过临床数据集进行验证,细胞内多克索鲁比辛度的平均AAFE为1.98.
- 模拟确定了与特定剂量方案相关的潜在风险,并建议了减少AE的策略.
结论:
- PBPK建模提供了一个强大的工具,用于定量评估化疗诱导的细胞毒性.
- 研究结果支持已确定的多克索鲁比剂量方案 (75 mg/m2,21天间隔),并表明修改后的输液方法可以减少不良反应.
- 这项研究为优化多克索鲁比化疗和提高患者安全提供了宝贵的见解.
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