Identification

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Name
Tafamidis
Accession Number
DB11644
Type
Small Molecule
Groups
Approved, Investigational
Description

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

Structure
Thumb
Synonyms
  • Tafamidis
  • Tafamidisum
External IDs
FX-006 / FX-1005 / FX-1006 / FX006 / FX1006
Product Ingredients
IngredientUNIICASInChI Key
Tafamidis meglumineZU7CF08A1A951395-08-7DQJDBUPLRMRBAB-WZTVWXICSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VyndamaxCapsule, liquid filled61 mg/1OralPfizer Laboratories Div Pfizer Inc2019-08-27Not applicableUs
VyndaqelCapsule20 mgOralPfizer2011-11-16Not applicableEu
VyndaqelCapsule, liquid filled20 mg/1OralPfizer Laboratories Div Pfizer Inc2019-05-16Not applicableUs
VyndaqelCapsule20 mg/1OralPfizer Labs Division of Pfizer Inc.2015-12-15Not applicableUs
VyndaqelCapsule20 mgOralPfizer2011-11-16Not applicableEu
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
8FG9H9D31J
CAS number
594839-88-0
Weight
Average: 308.116
Monoisotopic: 306.980298509
Chemical Formula
C14H7Cl2NO3
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

Pharmacology

Indication

Tafamidis is indicated to treat cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults.2,3,7

Associated Conditions
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
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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

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

Affected organisms
  • Humans and other mammals
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.
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.
AlvocidibThe serum concentration of Alvocidib can be increased when it is combined with Tafamidis.
ApixabanThe serum concentration of Apixaban can be increased when it is combined with Tafamidis.
BrigatinibThe serum concentration of Brigatinib can be increased when it is combined with Tafamidis.
CamptothecinThe serum concentration of Camptothecin can be increased when it is combined with Tafamidis.
CelecoxibThe serum concentration of Celecoxib can be increased when it is combined with Tafamidis.
CerivastatinThe serum concentration of Cerivastatin can be increased when it is combined with Tafamidis.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
Not Available

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. [PubMed:26894299]
  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. [PubMed:31913401]
  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. [PubMed:31735731]
  4. Ratner M: Spotlight focuses on protein-misfolding therapies. Nat Biotechnol. 2009 Oct;27(10):874. doi: 10.1038/nbt1009-874c. [PubMed:19816426]
  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. [PubMed:28803538]
  6. Tafamadis SmPC EMA [Link]
  7. FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules [Link]
External Links
KEGG Drug
D09673
PubChem Compound
11001318
PubChem Substance
347828016
ChemSpider
9176510
BindingDB
50197883
ChEBI
78538
ChEMBL
CHEMBL2103837
ZINC
ZINC000043206271
HET
3MI
Wikipedia
Tafamidis
ATC Codes
N07XX08 — 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
1CompletedBasic ScienceHealthy Volunteers9
1CompletedBasic ScienceTTR Cardiomyopathy2
1Not Yet RecruitingBasic ScienceHealthy Volunteers1
1RecruitingBasic ScienceHealthy Volunteers1
2CompletedTreatmentBilateral Knee Osteoarthritis1
2CompletedTreatmentKnee Osteoarthritis (Knee OA)5
2CompletedTreatmentKnee Osteoarthritis (Knee OA) / Type 2 Diabetes Mellitus1
2CompletedTreatmentOsteoarthritis of the Hip / Osteoarthritis of the Shoulder1
2RecruitingOtherOsteoarthritis, Hip1
2RecruitingTreatmentAdhesive Capsulitis / Osteoarthritis of the Shoulder1
2TerminatedTreatmentPost-traumatic Osteoarthritis of the Knee1
3Active Not RecruitingTreatmentATTR-PN1
3Active Not RecruitingTreatmentKnee Osteoarthritis (Knee OA)1
3Active Not RecruitingTreatmentOsteoarthritis, Hip1
3CompletedTreatmentKnee Osteoarthritis (Knee OA)2
3CompletedTreatmentTTR-CM1
3CompletedTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
3CompletedTreatmentTransthyretin Familial Amyloid Polyneuropathy1
3RecruitingTreatmentGlucocorticoid therapy / Injections / Rotator Cuff Impingement / Rotator Cuff Tears / Rotator Cuff Tendinitis1
3RecruitingTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
4RecruitingTreatmentKnee Osteoarthritis (Knee OA)1
Not AvailableActive Not RecruitingNot AvailableTransthyretin Familial Amyloid Poluneuropathy1
Not AvailableRecruitingNot AvailableTransthyretin (TTR) Amyloid Cardiomyopathy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, liquid filledOral61 mg/1
CapsuleOral20 mg
CapsuleOral20 mg/1
Capsule, liquid filledOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7214696No2007-05-082023-12-19Us
US9770441No2017-09-262035-08-31Us
US8653119No2014-02-182024-01-28Us
US7214695No2007-05-082024-04-27Us
US8168663No2012-05-012023-12-19Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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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

Taxonomy

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
Phenyl-1,3-oxazole / Benzoxazole / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Heteroaromatic compound
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
1,3-benzoxazoles, monocarboxylic acid, dichlorobenzene (CHEBI:78538)

Targets

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. [PubMed:31735731]
  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 15:30 / Updated on February 06, 2020 13:11