1型ifn介导的系统性红斑狼疮炎症的综合机制模型。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Alina Volkova, Victor Sokolov, Florencia Tettamanti, Meghna Verma, Yaroslav Ugolkov, Kirill Peskov, Weifeng Tang, Holly Kimko
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引用次数: 0

摘要

I型干扰素(IFN1)途径靶向治疗是治疗系统性红斑狼疮的一种非常有前途的疗法。然而,这些化合物的总体临床效益受到显著可变性的影响。在本研究中,我们建立了I型ifn介导炎症的定量系统药理学模型,并应用该模型间接比较了anifrolumab、sifalimumab、daxdilimab和litfilimab的药理学反应,模型中以IFN1基因标记(IFNGS)的变化为代表。该模型由20个常微分方程和68个参数组成,其中4个系统参数(包括1个随机效应)使用来自IIb期anifrolumab临床试验的患者水平数据进行估计。靶标内和通路内验证使用研究水平的药代动力学、IFNα和/或IFNGS数据进行,这些数据来自5个anifrolumab、4个sifalimumab、1个daxdilimab和1个litfilimab试验。该模型成功捕获了这些化合物在临床相关剂量下IFNGS的总体趋势,并区分了低(
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An Integrative Mechanistic Model of Type 1 IFN-Mediated Inflammation in Systemic Lupus Erythematosus.

Type I interferon (IFN1) pathway-targeting therapies represent a highly promising class of remedies for the treatment of systemic lupus erythematosus. However, the overall clinical benefit of these compounds is afflicted by marked variability. In this study, we developed a quantitative systems pharmacology model of type I IFN-mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient-level data from Phase IIb anifrolumab clinical trial. Within-target and within-pathway validation was performed using study-level pharmacokinetics, IFNα, and/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (< 2.75) and high (≥ 2.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100-150 mg every 4 weeks). In contrast, IFNGS response under 150 mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFNα biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFNα, and IFNα fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (ΔIFNGS~25%), which was further enhanced in patients with high baseline IFNGS or IFNα (ΔIFNGS~50%-60%).

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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