Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid.
Amyloid
; 30(3): 279-289, 2023 Sep.
Article
em En
| MEDLINE
| ID: mdl-36691999
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 â¼125 nM. By linear extrapolation, we expect a CSF concentration of â¼500 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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neuropatias Amiloides Familiares
/
Cardiomiopatias
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article