Tafamidis
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Identification
- Summary
Tafamidis is a medication used to treat transthyretin-mediated amyloidosis.
- Brand Names
- Vyndamax, Vyndaqel
- Generic Name
- Tafamidis
- DrugBank Accession Number
- DB11644
- Background
Tafamidis and tafamidis meglumine (FX-1006A) are benzoxazole derivatives1 developed by FoldRX.4 Tafamidis is structurally similar to diflusinal.4
Tafamidis was granted an EMA market authorisation on 16 November 20116 and FDA approval on 3 May 2019.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 308.116
Monoisotopic: 306.980298509 - Chemical Formula
- C14H7Cl2NO3
- Synonyms
- Tafamidis
- Tafamidisum
- External IDs
- FX-006
- FX-1005
- FX-1006
- FX006
- FX1006
Pharmacology
- Indication
Tafamidis is indicated to treat cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults.2,3,7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Cardiomyopathy •••••••••••• ••••• ••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Tafamidis stabilizes transthyretin tetramers, reducing the amount of monomers available for amyloidogenesis.7 It has a long duration of action as it is given once daily, and a wide therapeutic window.7
- Mechanism of action
Genetic mutations or natural misfolding of transthyretin destabalizes transthyretin tetramers, leading to their dissociation and aggregation in tissues, and disrupting the normal function of these tissues.3,1 Tafamidis binds to transthyretin tetramers at the thyroxin binding sites, stabilizing the tetramer, reducing the availability of monomers for amyloidogenesis.1,6,7
Target Actions Organism ATransthyretin chaperoneHumans - Absorption
Tafamidis reaches a Cmax of 1430.93ng/mL with a Tmax of 1.75h fasted and 4h fed.1 The AUC of tafamidis is 47,864.31ng*h/mL.1
- Volume of distribution
The apparent volume of distribution at steady state is 18.5L.7
- Protein binding
Tafamidis 99.9% protein bound in plasma, mostly to transthyretin.7
- Metabolism
Tafamidis is largely not subject to first pass or oxidative metabolism, being 90% unchanged after in in vitro experiments.5 Preclinical data suggest tafamidis is mainly metabolized through glucuronidation and excreted in bile.7
- Route of elimination
A 20mg oral dose of tafamidis is approximately 59% recovered in the feces, largely as unchanged drug.7 Approximately 22% of a 20mg oral dose is recovered in the urine, mostly as the glucuronide metabolite.7
- Half-life
The half life of tafamidis is 49h.7
- Clearance
The oral clearance of tafamidis is 0.263L/h.7 The apparent total clearance is 0.44L/h.1
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Data regarding overdoses of tafamidis are not readily available.7 In a clinical trial, some patients were given up to 6 times the normal dose with one reported case of mild hordeolum.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Tafamidis. Acamprosate The excretion of Acamprosate can be decreased when combined with Tafamidis. Acyclovir The excretion of Acyclovir can be decreased when combined with Tafamidis. Adefovir dipivoxil The excretion of Adefovir dipivoxil can be decreased when combined with Tafamidis. Afatinib The serum concentration of Afatinib can be increased when it is combined with Tafamidis. - Food Interactions
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Tafamidis meglumine ZU7CF08A1A 951395-08-7 DQJDBUPLRMRBAB-WZTVWXICSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vyndamax Capsule 61 mg Oral Pfizer Italia S.R.L. 2021-09-15 Not applicable Canada Vyndamax Capsule, liquid filled 61 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2019-08-27 Not applicable US Vyndaqel Capsule 61 mg Oral Pfizer Europe Ma Eeig 2020-12-23 Not applicable EU Vyndaqel Capsule, liquid filled 20 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2019-05-16 Not applicable US Vyndaqel Capsule 20 mg Oral Pfizer Europe Ma Eeig 2016-09-08 Not applicable EU
Categories
- ATC Codes
- N07XX08 — Tafamidis
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenyl-1,3-oxazoles. These are aromatic heterocyclic compounds containing a 1,3-oxazole substituted at one or more positions by a phenyl group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Azoles
- Sub Class
- Oxazoles
- Direct Parent
- Phenyl-1,3-oxazoles
- Alternative Parents
- Benzoxazoles / Dichlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds show 4 more
- Substituents
- 1,3-dichlorobenzene / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Benzoxazole / Carboxylic acid / Carboxylic acid derivative / Chlorobenzene show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- 1,3-benzoxazoles, monocarboxylic acid, dichlorobenzene (CHEBI:78538)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 8FG9H9D31J
- CAS number
- 594839-88-0
- InChI Key
- TXEIIPDJKFWEEC-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H7Cl2NO3/c15-9-3-8(4-10(16)6-9)13-17-11-2-1-7(14(18)19)5-12(11)20-13/h1-6H,(H,18,19)
- IUPAC Name
- 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
- SMILES
- OC(=O)C1=CC=C2N=C(OC2=C1)C1=CC(Cl)=CC(Cl)=C1
References
- General References
- Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, Maurer MS, Plante-Bordeneuve V, Labaudiniere R, Mundayat R, Riley S, Lombardo I, Huertas P: Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 2016 Jun;5(1):1-25. doi: 10.1007/s40120-016-0040-x. Epub 2016 Feb 19. [Article]
- Gurwitz JH, Maurer MS: Tafamidis-A Pricey Therapy for a Not-So-Rare Condition. JAMA Cardiol. 2020 Jan 8. pii: 2758314. doi: 10.1001/jamacardio.2019.5233. [Article]
- Endo J, Sano M, Izumiya Y, Tsujita K, Nakamura K, Tahara N, Kuwahara K, Inomata T, Ueda M, Sekijima Y, Ando Y, Tsutsui H, Isobe M, Fukuda K: A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. Circ J. 2019 Dec 25;84(1):15-17. doi: 10.1253/circj.CJ-19-0811. Epub 2019 Nov 16. [Article]
- Ratner M: Spotlight focuses on protein-misfolding therapies. Nat Biotechnol. 2009 Oct;27(10):874. doi: 10.1038/nbt1009-874c. [Article]
- Lee KR, Jeong JW, Hyun HC, Jang E, Ahn S, Choi S, Joo SH, Kim S, Koo TS: Pharmacokinetics of tafamidis, a transthyretin amyloidosis drug, in rats. Xenobiotica. 2018 Aug;48(8):831-838. doi: 10.1080/00498254.2017.1366575. Epub 2017 Nov 16. [Article]
- Tafamadis SmPC EMA [Link]
- FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules [Link]
- External Links
- PDB Entries
- 3tct / 4his / 6e6z / 6e72 / 6e74 / 6e77 / 6fft
- FDA label
- Download (752 KB)
- MSDS
- Download (24.8 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Transthyretin (TTR) Amyloid Cardiomyopathy 2 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM) 1 somestatus stop reason just information to hide Not Available Completed Not Available Hereditary Transthyretin Amyloidosis (ATTRv) Cardiomyopathy (CM), Mixed Phenotype 1 somestatus stop reason just information to hide Not Available Completed Not Available Hereditary Transthyretin Amyloidosis (ATTRv) / Polyneuropathies 1 somestatus stop reason just information to hide Not Available Completed Not Available Transthyretin Familial Amyloid Poluneuropathy 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 61 mg Capsule, liquid filled Oral 61 mg/1 Capsule, liquid filled Oral 61 mg Capsule Oral 61.0 mg Capsule Oral 20 mg/1 Capsule Oral 20 mg Capsule, liquid filled Oral 20 mg/1 Capsule, liquid filled Oral 20 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7214696 No 2007-05-08 2023-12-19 US US9770441 No 2017-09-26 2035-08-31 US US8653119 No 2014-02-18 2024-01-28 US US7214695 No 2007-05-08 2024-04-27 US US8168663 No 2012-05-01 2023-12-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility >50mg/mL ChemSpider - Predicted Properties
Property Value Source Water Solubility 0.0323 mg/mL ALOGPS logP 3.91 ALOGPS logP 4.21 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 3.6 Chemaxon pKa (Strongest Basic) -0.4 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 63.33 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 84.69 m3·mol-1 Chemaxon Polarizability 29.74 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-052r-2093000000-6c9eda1b616978583c87 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0039000000-1f38dad1bb25c8618ce8 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0039000000-e8fbf16716d0214376d8 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-0090000000-ecc48e32d0951c7054f5 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-01p9-0090000000-15c047cc68d3caa66bd6 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-0090000000-8b68e6bd6827ac1bb792 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-0090000000-a799a787fdd1b4a03069 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 162.78645 predictedDeepCCS 1.0 (2019) [M+H]+ 165.14464 predictedDeepCCS 1.0 (2019) [M+Na]+ 171.31013 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Chaperone
- General Function
- Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain
- Specific Function
- hormone activity
- Gene Name
- TTR
- Uniprot ID
- P02766
- Uniprot Name
- Transthyretin
- Molecular Weight
- 15886.88 Da
References
- Endo J, Sano M, Izumiya Y, Tsujita K, Nakamura K, Tahara N, Kuwahara K, Inomata T, Ueda M, Sekijima Y, Ando Y, Tsutsui H, Isobe M, Fukuda K: A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. Circ J. 2019 Dec 25;84(1):15-17. doi: 10.1253/circj.CJ-19-0811. Epub 2019 Nov 16. [Article]
- FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Tafamadis SmPC EMA [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- Tafamadis SmPC EMA [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- Tafamadis SmPC EMA [Link]
Drug created at October 17, 2016 21:30 / Updated at April 23, 2024 11:38