基于生理学的药物动力学模型与反向剂量方法相结合,研究tacrolimus的毒性耐受剂量
Limin Cai1,2, Meng Ke1,2, Han Wang1,2
1Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China.
Archives of toxicology
|August 12, 2023
概括
这项研究确定了考虑到毒性,CYP3A5遗传学和肝功能的安全塔克罗利斯 (TAC) 剂量. 生理学药物动力学建模确定了个性化的耐受性TAC剂量,以尽量减少移植患者的毒性.
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
- 遗传学 是一个遗传学.
背景情况:
- 塔克罗利 (TAC) 对于移植后的免疫抑制至关重要,但其临床使用因毒性而受到限制.
- 根据CYP3A5基因型和肝功能了解TAC的耐受剂量对于患者的安全至关重要.
研究的目的:
- 为了探索不同CYP3A5基因型和肝脏疾病的个体中塔克罗 (TAC) 诱导的毒性,耐受剂量.
- 在特定患者群体中建立安全TAC剂量的预测模型.
主要方法:
- 开发并验证了一种人体全身生理学药理动力学 (WB-PBPK) 模型.
- 构建了一种大鼠PBPK模型,将其转换为人类脏PBPK模型,并推断出体外毒性数据 (BMCL5).
- 用于体外-体外抽取 (IVIVE) 来确定不同人群的口服剂量方案.
主要成果:
- 生理学药动力学 (PBPK) 建模表明,在健康受试者和不同程度的肝功能衰竭中,对CYP3A5表达体和非表达体的特定耐受性TAC剂量.
- 耐受剂量随着肝功能衰竭的增加而显著降低,对于严重肝功能衰竭的CYP3A5表达体而言,相比于非表达体,所需的剂量更低.
- 该研究为不同患者组确定了一系列安全的TAC剂量 (mg/kg),突出显示中度至重度肝功能障碍患者耐受剂量的显著降低.
结论:
- 联合使用PBPK建模和IVIVE是有效的预测药物耐受剂量在特定人群.
- 这种方法可以指导个性化塔克罗利斯 (TAC) 剂量策略,以减轻移植患者的毒性.
- 基于CYP3A5基因型和肝功能的个性化剂量对于优化塔克罗利斯治疗和患者结果至关重要.
关键词:
在IVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIVIV毒性 毒性 毒性基于生理学的药理动力学 药理动力学塔克罗利慕斯可以使用.
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