Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid.

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Felix J Tsai, Marcus Jaeger, Teresa Coelho, Evan T Powers, Jeffery W Kelly
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引用次数: 0

Abstract

Background: Hereditary transthyretin (TTR) amyloidosis (ATTRv) initially presents as a polyneuropathy and/or a cardiomyopathy. Central nervous system (CNS) pathology in ATTRv amyloidosis, including focal neurological episodes, dementia, cerebrovascular bleeding, and seizures, appears around a decade later. Wild-type (WT) TTR amyloidosis (ATTRwt) causes a cardiomyopathy. CNS pathology risk likely also increases in these patients as cardiomyopathy progresses. Herein, we study tafamidis-mediated TTR kinetic stabilisation in cerebrospinal fluid (CSF).

Methods: Varying tafamidis concentrations (50-1000 nM) were added to CSF from healthy donors or ATTRv patients, and TTR stabilisation was measured via the decrease in dissociation rate.

Results: Tafamidis meglumine (Vyndaqel) can be dosed at 20 or 80 mg QD. The latter dose is bioequivalent to a 61 mg QD dose of tafamidis free acid (Vyndamax). The tafamidis CSF concentration in ATTRv patients on 20 mg Vyndaqel is ∼125 nM. By linear extrapolation, we expect a CSF concentration of ∼500 nM at the higher dose. When tafamidis is added to healthy donor CSF at 125 or 500 nM, the WT TTR dissociation rate decreases by 42% or 87%, respectively.

Conclusions: Tafamidis stabilises TTR in CSF to what is likely a clinically meaningful extent at CSF concentrations achieved by the normal tafamidis dosing regimen.

脑脊液中转甲状腺素稳定所需的Tafamidis浓度。
背景:遗传性转甲状腺素(TTR)淀粉样变性(ATTRv)最初表现为多发性神经病和/或心肌病。ATTRv淀粉样变性的中枢神经系统(CNS)病理,包括局灶性神经系统发作、痴呆、脑血管出血和癫痫发作,出现在大约十年后。野生型(WT)TTR淀粉样变性(ATTRwt)引起心肌病。随着心肌病的进展,这些患者的中枢神经系统病理风险可能也会增加。在此,我们研究了tafamidis介导的脑脊液(CSF)TTR动力学稳定。方法:不同浓度(50-1000 nM)添加到来自健康供体或ATTRv患者的CSF中,并且通过解离率的降低来测量TTR的稳定。结果:甲葡胺可在20或80时给药 mg每日一次。后一种剂量与61 mg每日一次剂量的塔夫酰胺游离酸(Vyndamax)。20日ATTRv患者的tafamidis CSF浓度 mg Vyndaquel为~125 nM。通过线性外推,我们预计CSF浓度为~500 nM。当在125或500下将太酰胺添加到健康供体CSF中时 nM时,WT TTR解离率分别降低42%或87%。结论:在正常的Tafamidis给药方案达到的CSF浓度下,tafamidi稳定CSF中的TTR达到可能具有临床意义的程度。
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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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