A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Dan Sexton, Hoa Q Nguyen, Salomé Juethner, Haobin Luo, Zhiwei Zhang, Paul Jasper, Andy Z X Zhu
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Abstract

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.

Abstract Image

遗传性血管性水肿中血浆激肽-激肽系统失调的定量系统药理学模型。
因 C1 抑制剂缺乏而导致的遗传性血管性水肿(HAE)是一种罕见的、使人衰弱的遗传性疾病,其特征是反复发作、难以预测的水肿。HAE 的临床症状源于血浆降钙素-激肽系统(KKS)失调导致的缓激肽生成过多。根据因子 XII (FXII) 自激活到激活的 FXII (FXIIa),导致前allikrein 产生allikrein,从而引发 HAE 发作的原理,我们开发了一个定量系统药理学 (QSP) 模型,从机理上描述了 KKS 及其在 HAE 病理生理学中的作用。根据文献数据和测量HAE患者或接受拉那珠单抗治疗的健康志愿者血浆中凯利克瑞林活性抑制作用的体内外试验,我们构建了一个基础药效学模型并对其进行了参数化。使用虚拟患者群体模拟 HAE 发作,当全身缓激肽水平超过 20 pM 时记录发作情况。通过将模拟结果与拉那珠单抗和血浆衍生 C1 抑制剂临床试验的观察结果进行比较,对模型进行了验证。随后,该模型被用于分析不坚持每日口服预防性疗法的影响;模拟结果显示,每月漏服次数与药效降低之间存在相关性。此外,还研究了将拉那珠单抗的给药频率从每两周(Q2W)300 毫克降低到每四周(Q4W)300 毫克的影响,结果表明,虽然 Q4W 给药可大幅降低发病率,但 Q2W 给药的降低幅度更大。总之,QSP 模型与临床数据显示出良好的一致性,可用于假设检验和结果预测。
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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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