Tafamidis

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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
ATransthyretin
chaperone
Humans
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
Adverseeffects
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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.
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Tafamidis.
AcamprosateThe excretion of Acamprosate can be decreased when combined with Tafamidis.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Tafamidis.
Adefovir dipivoxilThe excretion of Adefovir dipivoxil can be decreased when combined with Tafamidis.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Tafamidis.
AllopurinolThe serum concentration of Allopurinol can be increased when it is combined with Tafamidis.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Tafamidis.
AlprostadilThe excretion of Alprostadil can be decreased when combined with Tafamidis.
Aminohippuric acidThe excretion of Aminohippuric acid can be decreased when combined with Tafamidis.
ApixabanThe serum concentration of Apixaban can be increased when it is combined with Tafamidis.
Interactions
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Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Tafamidis meglumineZU7CF08A1A951395-08-7DQJDBUPLRMRBAB-WZTVWXICSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VyndamaxCapsule, liquid filled61 mg/1OralPfizer Laboratories Div Pfizer Inc2019-08-27Not applicableUS flag
VyndamaxCapsule61 mgOralPfizer Canada Ulc2021-09-15Not applicableCanada flag
VyndaqelCapsule61 mgOralPfizer Europe Ma Eeig2020-12-23Not applicableEU flag
VyndaqelCapsule20 mg/1OralPfizer Labs Division of Pfizer Inc.2015-12-15Not applicableUS flag
VyndaqelCapsule20 mgOralPfizer Canada Ulc2020-04-07Not applicableCanada flag
VyndaqelCapsule20 mgOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
VyndaqelCapsule61 mgOralPfizer Europe Ma Eeig2020-12-23Not applicableEU flag
VyndaqelCapsule, liquid filled20 mg/1OralPfizer Laboratories Div Pfizer Inc2019-05-16Not applicableUS flag
VyndaqelCapsule20 mgOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag

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
  1. 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]
  2. 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]
  3. 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]
  4. Ratner M: Spotlight focuses on protein-misfolding therapies. Nat Biotechnol. 2009 Oct;27(10):874. doi: 10.1038/nbt1009-874c. [Article]
  5. 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]
  6. Tafamadis SmPC EMA [Link]
  7. FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules [Link]
KEGG Drug
D09673
PubChem Compound
11001318
PubChem Substance
347828016
ChemSpider
9176510
BindingDB
50197883
RxNav
1545063
ChEBI
78538
ChEMBL
CHEMBL2103837
ZINC
ZINC000043206271
PDBe Ligand
3MI
Wikipedia
Tafamidis
PDB Entries
3tct / 4his / 6e6z / 6e72 / 6e74 / 6e77 / 6fft
FDA label
Download (752 KB)
MSDS
Download (24.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentOsteoarthritis of the Knee1
4RecruitingTreatmentTransthyretin Amyloid Cardiomyopathy1
4RecruitingTreatmentTransthyretin Amyloid Polyneuropathy (ATTR-PN)1
4RecruitingTreatmentTransthyretin Amyloidosis1
3Active Not RecruitingTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
3CompletedTreatmentATTR-CM / TTR-CM1
3CompletedTreatmentATTR-PN1
3CompletedTreatmentOsteoarthritis of the Knee3
3CompletedTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
3CompletedTreatmentTransthyretin Familial Amyloid Polyneuropathy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, liquid filledOral61 mg/1
CapsuleOral61.0 mg
CapsuleOral20 MG
CapsuleOral20 mg/1
CapsuleOral61 MG
Capsule, liquid filledOral20 mg/1
Capsule, liquid filledOral20 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7214696No2007-05-082023-12-19US flag
US9770441No2017-09-262035-08-31US flag
US8653119No2014-02-182024-01-28US flag
US7214695No2007-05-082024-04-27US flag
US8168663No2012-05-012023-12-19US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>50mg/mLChemSpider
Predicted Properties
PropertyValueSource
Water Solubility0.0323 mg/mLALOGPS
logP3.91ALOGPS
logP4.21ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)3.6ChemAxon
pKa (Strongest Basic)-0.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.33 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity84.69 m3·mol-1ChemAxon
Polarizability29.74 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Chaperone
General Function
Identical protein binding
Specific Function
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Gene Name
TTR
Uniprot ID
P02766
Uniprot Name
Transthyretin
Molecular Weight
15886.88 Da
References
  1. 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]
  2. FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Tafamadis SmPC EMA [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Tafamadis SmPC EMA [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Tafamadis SmPC EMA [Link]

Drug created on October 17, 2016 21:30 / Updated on October 22, 2021 23:18