clinical trial was 480 mg as a single dose. There was one reported adverse event of mildhordeolum at this dose.
11. DESCRIPTION
VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) contain tafamidis as the active moiety,which is a selective stabilizer of transthyretin.
The chemical name of tafamidis meglumine is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acidmono (1-deoxy-1-methylamino-D-glucitol). The molecular formula is C14H7Cl2NO3 C7H17NO5, and themolecular weight is 503.33 g/mol. The structural formula is:
Tafamidis meglumine 20-mg soft gelatin capsule for oral use contains a white to pink colored suspension oftafamidis meglumine 20 mg (equivalent to 12.2 mg of tafamidis free acid), and the following inactiveingredients: ammonium hydroxide 28%, brilliant blue FCF, carmine, ethyl alcohol, gelatin, glycerin, iron oxide(yellow), isopropyl alcohol, polyethylene glycol 400, polysorbate 80, polyvinyl acetate phthalate, propyleneglycol, purified water, sorbitan monooleate, sorbitol, and titanium dioxide.
The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecularformula is C14H7Cl2NO3, and the molecular weight is 308.12 g/mol. The structural formula is:Tafamidis 61-mg soft gelatin capsule for oral use contains a white to pink colored suspension of tafamidis61 mg and the following inactive ingredients: ammonium hydroxide 28%, butylated hydroxytoluene, ethylalcohol, gelatin, glycerin, iron oxide (red), isopropyl alcohol, polyethylene glycol 400, polysorbate 20, povidone(K-value 90), polyvinyl acetate phthalate, propylene glycol, purified water, sorbitol, and titanium dioxide.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tafamidis is a selective stabilizer of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilizing thetetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
12.2 Pharmacodynamics
A proprietary TTR stabilization assay was utilized as a pharmacodynamic marker and assessed the stability ofthe TTR tetramer ex vivo. The TTR stabilization assay quantifies immunoturbidimetric measurement of thestable TTR tetramer in plasma pre- and post-treatment with 2-day in vitro denaturation with urea. Using this
proprietary assay, a dose-dependent trend for greater TTR tetramer stabilization is observed for VYNDAQEL80-mg compared to VYNDAQEL 20-mg. However, the clinical relevance of a higher TTR tetramerstabilization towards cardiovascular outcomes is not known.
VYNDAQEL stabilized both the wild type TTR tetramer and the tetramers of 14 TTR variants tested clinicallyafter once-daily dosing. Tafamidis also stabilized the TTR tetramer for 25 variants tested ex vivo.
VYNDAQEL and VYNDAMAX may decrease serum concentrations of total thyroxine, without anaccompanying change in thyroid stimulating hormone (TSH). This reduction in total thyroxine values isprobably the result of reduced thyroxine binding to or displacement from transthyretin (TTR) due to the highbinding affinity of tafamidis to the TTR thyroxine receptor. No corresponding clinical findings consistent withhypothyroidism have been observed.
Biomarkers associated with heart failure (NT-proBNP and Troponin I) favored VYNDAQEL over placebo.
Cardiac Electrophysiology
At approximately 2.2 times the steady state peak plasma concentration (Cmax) at the recommended dose |
