Tafamidis meglumine

Tafamidis meglumine, also known as PF-06291826 and Vyndaqel, is the 1:1 meglumine salt of tafamidis, a selective transthyretin (TTR) stabilizer. Its molecular formula is C21H24Cl2N2O8, and the tafamidis meglumine molecular weight is 503.33 g/mol. CAS 951395-08-7 identifies this salt and distinguishes it from tafamidis free acid, which has a different CAS number and molecular weight.

Application of Tafamidis meglumine

Tafamidis meglumine is used to investigate kinetic stabilization of the TTR tetramer as a way to limit amyloidogenic misfolding. Applications include TTR-binding studies, tetramer-stability assays, fibril-formation experiments, and comparisons of wild-type TTR with disease-associated variants. Assay concentrations should clearly state whether they represent the salt or tafamidis equivalents.

In Vitro

Isothermal titration calorimetry showed that tafamidis binds the two thyroxine-binding sites of tetrameric TTR with Kd values of approximately 3 and 278 nM, reflecting negative cooperativity.

In an acid-mediated assay, tafamidis inhibited fibril formation by wild-type, V30M, and V122I TTR with EC50 values of 2.7–3.2 μM. This corresponded to tafamidis:TTR ratios of 0.75–0.90. The 72-hour experiment used 0–7.2 μM tafamidis at pH 4.4–4.5. These measurements describe the tafamidis active moiety; meglumine is the counterion rather than the TTR-binding component.

In Vivo

ATTR-ACT enrolled 441 patients with wild-type or hereditary transthyretin amyloid cardiomyopathy. Participants received 20 or 80 mg of tafamidis meglumine or placebo for 30 months. Pooled tafamidis treatment reduced all-cause mortality from 42.9% to 29.5% and the annual cardiovascular-related hospitalization rate from 0.70 to 0.48.

In the United States, Vyndaqel 80 mg once daily and Vyndamax 61 mg once daily are approved for adults with wild-type or hereditary ATTR cardiomyopathy. Vyndaqel contains the meglumine salt, whereas Vyndamax contains tafamidis free acid; they are not substitutable per milligram. In the EU, Vyndaqel is also authorised for adults with stage 1 symptomatic ATTR polyneuropathy.

Biochemical and Physiological Actions

TTR is a tetrameric transport protein for thyroxine and retinol-binding protein. Tetramer dissociation into monomers is the rate-limiting step in the amyloidogenic pathway. Tafamidis occupies the normally unoccupied thyroxine-binding sites at the dimer–dimer interface, increasing the kinetic barrier to dissociation and reducing formation of misfolded monomers.

Within the tafamidis meglumine structure, the tafamidis ion provides TTR-stabilizing activity, while meglumine provides the salt-forming counterion. Stabilization has been demonstrated with wild-type TTR and multiple variants, but results remain dependent on the assay and variant tested.

Features and Benefits of Tafamidis meglumine

• Defined 1:1 tafamidis meglumine chemical structure.
• Nanomolar binding at both TTR thyroxine-binding sites.
• In vitro data for wild-type and amyloidogenic TTR variants.
• Phase 3 outcome data and distinct regulatory formulations.

For experimental use, verify identity, assay, and salt basis against the product-specific CoA. Registry number 951395-08-7 should not be used interchangeably with the CAS number of tafamidis free acid.