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.

中文翻译：

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脑脊液中转甲状腺素蛋白稳定所需的 Tafamidis 浓度

摘要

背景

遗传性转甲状腺素蛋白 (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) 病理学，包括局灶性神经系统发作、痴呆、脑血管出血和癫痫发作，大约在十年后出现。野生型 (WT) TTR 淀粉样变性 (ATTRwt) 会导致心肌病。随着心肌病的进展，这些患者的中枢神经系统病理风险也可能增加。在此，我们研究了 tafamidis 介导的脑脊液 (CSF) 中 TTR 动力学稳定性。

方法

将不同浓度的tafamidis（50-1000 nM）添加到来自健康供体或ATTRv患者的CSF中，并通过解离率的降低来测量TTR稳定性。

结果

Tafamidis meglumine (Vyndaqel) 每日剂量为 20 或 80 mg。后一剂量与 61 mg QD 剂量的 tafamidis 游离酸 (Vyndamax) 生物等效。ATTRv 患者服用 20 mg Vyndaqel 后，tafamidis CSF 浓度约为 125 nM。通过线性外推，我们预计较高剂量下的 CSF 浓度约为 500 nM。当将 125 或 500 nM 的 tafamidis 添加到健康供体 CSF 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，Tafamidis 将 CSF 中的 TTR 稳定到可能具有临床意义的程度。