Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy.

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
David A Tess, Tristan S Maurer, Zhenhong Li, Christine Bulawa, James Fleming, Amy T Moody
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引用次数: 2

Abstract

Background: Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.

Methods: We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression.

Results: Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation in vivo. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively.

Conclusions: These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism.

Clinicaltrials.gov identifier: NCT01994889.

他非他汀治疗的转甲状腺蛋白淀粉样心肌病患者结合位点占用、转甲状腺蛋白稳定和疾病改变的关系
背景:他法非地通过结合转甲状腺素(TTR)淀粉样心肌病(atr - cm)四聚体和抑制分解成能够变性和沉积在心脏组织的单体来抑制其进展。虽然3期atr - act试验证明了他法米地的有效性,但批准的剂量在多大程度上捕捉了该机制的全部潜力还有待评估。方法:我们建立了血浆中动态TTR浓度模型,将他非他胺类药物对TTR的占用与TTR的稳定联系起来。然后,我们开发了群体药代动力学-药效学模型来描述稳定性与疾病进展之间的关系。结果:对他非他胺暴露和血浆TTR增加的个体患者数据进行建模,证实单位点结合在体内提供了完全的四聚体稳定。据估计,批准的剂量可使未结合的TTR四聚体减少92%,NT-proBNP、KCCQ-OS和6分钟步行试验疾病进展指标的变化率分别降低53%、56%和49%。模拟完全TTR稳定预测的降幅分别为58%、61%和54%。结论:这些发现支持TTR稳定作为atr - cm临床有益治疗选择的价值,以及他非他司能实现该机制几乎全部治疗益处的能力。
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来源期刊
Amyloid-Journal of Protein Folding Disorders
Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学
CiteScore
10.60
自引率
10.90%
发文量
48
审稿时长
6-12 weeks
期刊介绍: Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.
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