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


Felix J Tsai, Marcus Jaeger, Teresa Coelho, Evan T Powers, Jeffery W Kelly. Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. 2023 Sep;30(3):279-289

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PMID: 36691999

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