Pharmacology
Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with familial amyloid polyneuropathy, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.The maximum plasma concentration is achieved around two hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine. Chemistry
The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecule has two crystalline forms and one amorphous form; it is manufactured in one of the possible crystalline forms. It is marketed as a meglumine salt. It is slightly soluble in water. History
The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit transthyretin fibril formation in the 1990s. : 210   Tafamidis was eventually discovered by Kellys team using a structure-based drug design strategy; the chemical structure was first published in 2003. In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of the Massachusetts Institute of Technology and the Whitehead Institute, and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010. FoldRx was acquired by Pfizer later that year.Tafamidis was approved by the European Medicines Agency in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis.
Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.The U.S. Food and Drug Administration considers tafamidis to be a first-in-class medication. Medical use
Tafamidis is used to delay nerve damage in adults who have transthyretin amyloidosis with polyneuropathy, or heart disease in adults who have transthyretin amyloidosis with cardiomyopathy. It is taken by mouth.Women should not get pregnant while taking it and should not breastfeed while taking it. People with familial amyloid polyneuropathy who have received a liver transplant should not take it. Adverse effects
More than 10% of people in clinical trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea. Interactions
Tafamidis does not appear to interact with cytochrome P450 but it inhibits ATP-binding cassette super-family G member 2, so is likely to affect the levels of certain drugs including methotrexate, rosuvastatin, and imatinib. It also inhibits organic anion transporter 1 and organic anion transporter 3/solute carrier family 22 member 8 so is likely to interact with non-steroidal anti-inflammatory agents and other drugs that rely on those transporters.