以生理学为基础的药理动力学模型与相对的转录学来评估anifrolumabb的组织分布和受体占用率
Pradeep Sharma1, David W Boulton2, Lynn N Bertagnolli2
1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
CPT: pharmacometrics & systems pharmacology
|October 3, 2024
概括
作为I型干扰素受体 (IFNAR1) 抑制剂的阿尼弗罗卢马布显示出有前途的药理动力学. 皮下注射可能为自身免疫性疾病治疗提供持续的IFNAR1占用.
科学领域:
- 药理学 药理学是指药理学的学科.
- 免疫学 免疫学 免疫学
- 计算生物学 计算生物学
背景情况:
- I型干扰素与SLE等自身免疫性疾病有关.
- 阿尼弗罗卢马布向的是I型干扰素受体 (IFNAR1).
- 静脉注射Anifrolumab已被批准用于中度至重度的SLE.
研究的目的:
- 开发一种基于人群生理学的药理动力学 (PBPK) 模型,用于anifrolumab.
- 为了整合IFNAR1表达分析的相对转录组学.
- 为了预测阿尼弗罗卢马布的药理动力学和组织分布.
主要方法:
- 使用anifrolumab特性和FcRn结合动力学构建了一个PBPK模型.
- 利用相对转录组学来评估IFNAR1在各种组织中的表达.
- 使用临床数据验证了PBPK模型和转录组学方法.
主要成果:
- 该PBPK模型预测了高局部阿尼弗罗卢马布度超过IFNAR1解离常数.
- 预计IFNAR1占用率高,用于IV和SC阿尼弗罗卢马布剂量.
- 每周120毫克的皮下阿尼弗罗卢马布预测IFNAR1占用比IV300毫克Q4W更持久.
结论:
- 与转录组学相结合的PBPK模型为模拟单克隆抗体药理动力学提供了一种新的方法.
- 预测的高组织度和持续的IFNAR1占用支持anifrolumab的疗效.
- 这些发现为新适应症中阿尼弗罗卢马布的剂量策略提供了信息.
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