Identification

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Name
Tezacaftor
Accession Number
DB11712
Type
Small Molecule
Groups
Approved, Investigational
Description

Tezacaftor is a drug of the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator class.10 It was developed by Vertex Pharmaceuticals and FDA approved in combination with ivacaftor to manage cystic fibrosis.14 This drug was approved by the FDA on February 12, 2018.15

Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes. CFTR is active in epithelial cells of organs such as of the lungs, pancreas, liver, digestive system, and reproductive tract. Alterations in the CFTR gene result in altered production, misfolding, or function of the protein and consequently abnormal fluid and ion transport across cell membranes.5,6 As a result, CF patients produce thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to complications such as infections, lung damage, pancreatic insufficiency, and malnutrition.7

Structure
Thumb
Synonyms
  • Tezacaftor
External IDs
VX 661 / VX-661 / VX661
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
SymdekoTezacaftor (50 mg/1) + Ivacaftor (75 mg/1) + Ivacaftor (75 mg/1)KitOralVertex Pharmaceuticals Incorporated2019-06-21Not applicableUs
SymdekoTezacaftor (100 mg/1) + Ivacaftor (150 mg/1) + Ivacaftor (150 mg/1)KitOralVertex Pharmaceuticals Incorporated2018-02-13Not applicableUs
SymdekoTezacaftor (100 mg) + Ivacaftor (150 mg) + Ivacaftor (150 mg)TabletOralVertex Pharmaceuticals Incorporated2018-06-28Not applicableCanada
TrikaftaTezacaftor (50 mg/1) + Elexacaftor (100 mg/1) + Ivacaftor (75 mg/1) + Ivacaftor (150 mg/1)OralVertex Pharmaceuticals Incorporated2019-10-21Not applicableUs
Categories
UNII
8RW88Y506K
CAS number
1152311-62-0
Weight
Average: 520.505
Monoisotopic: 520.182121086
Chemical Formula
C26H27F3N2O6
InChI Key
MJUVRTYWUMPBTR-MRXNPFEDSA-N
InChI
InChI=1S/C26H27F3N2O6/c1-24(2,13-33)22-8-14-7-18(17(27)10-19(14)31(22)11-16(34)12-32)30-23(35)25(5-6-25)15-3-4-20-21(9-15)37-26(28,29)36-20/h3-4,7-10,16,32-34H,5-6,11-13H2,1-2H3,(H,30,35)/t16-/m1/s1
IUPAC Name
1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide
SMILES
CC(C)(CO)C1=CC2=CC(NC(=O)C3(CC3)C3=CC=C4OC(F)(F)OC4=C3)=C(F)C=C2N1C[C@@H](O)CO

Pharmacology

Indication

Tezacaftor is combined with ivacaftor in one product for the treatment of cystic fibrosis (CF) in patients aged 12 years or older with two copies of the F508del gene mutation or at least one mutation in the CFTR gene that is responsive to this drug.14

Tezacaftor, when used in combination with ivacaftor and elexacaftor in the product Trikafta, is also indicated for the treatment of CF in patients 12 years of age and older that have at least one F508del mutation in the CFTR gene.19

Associated Conditions
Pharmacodynamics

Clinical studies have shown a significant decrease in sweat chloride and an increase in the forced expiratory volume (FEV), a measure of lung function, following Tevacaftor/Ivacaftor therapy.1 Phase 3 clinical studies have shown that a significant increase in forced expiratory volume was attained at 4 and 8 weeks after initiating this drug. The above effects lead to improvement of the respiratory symptoms of cystic fibrosis. Tezacaftor does not induce clinically significant QT prolongation.2 When given with ivacaftor, tezacaftor can lead to liver transaminase elevations.14 Testing of transaminases (ALT and AST) levels should occur before starting this combination every 3 months during the first year of treatment, and every year afterwards. Patients with a history of transaminase elevations should be monitored more frequently.14

Mechanism of action

The transport of charged ions across cell membranes is normally achieved through the actions of the cystic fibrosis transmembrane regulator (CFTR) protein. This protein acts as a channel and allows for the passage of chloride and sodium. This process affects the movement of water in and out of the tissues and impacts the production of mucus that lubricates and protects certain organs and body tissues, including the lungs. In the F508del mutation of the CFTR gene, one amino acid is deleted at the position 508, therefore, the CFTR channel function is compromised, resulting in thickened mucus secretions.10 CFTR correctors such as tezacaftor aim to repair F508del cellular misprocessing.9 This is done by modulating the position of the CFTR protein on the cell surface to the correct position, allowing for adequate ion channel formation and increased in water and salt movement through the cell membrane.10 The concomitant use of ivacaftor is intended to maintain an open channel, increasing the transport of chloride, reducing thick mucus production.13

TargetActionsOrganism
ACystic fibrosis transmembrane conductance regulator
activator
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

The Cmax, Tmax and AUC of tezacaftor, when administered with ivacaftor, are 5.95 mcg/ml, 2-6 h, and 84.5 mcg.h/ml respectively.14 Exposure of tezacaftor/ivacaftor increases 3-fold when it is administered with a high-fat meal.14

Volume of distribution

The apparent volume of distribution of tezacaftor was 271 L in a study of patients in the fed state who received 100 mg of tezacaftor every 12 hours.14

Protein binding

Tezacaftor is approximately 99% bound to plasma proteins, mainly albumin.14

Metabolism

Tezacaftor is metabolized extensively in humans by the action of CYP3A4 and CYP3A5. There are three main circulating metabolites; M1, M2, and M5. The M1 is an active metabolite with similar activity to the parent drug, tezacaftor. The M2 metabolite is significantly less active and M5 is considered an inactive metabolite.4,14 An additional circulating metabolite, M3, corresponding to the glucuronide form of tezacaftor.14

Route of elimination

After oral administration, the majority of tezacaftor dose (72%) is found excreted in the feces either unchanged or as its metabolite, M2. About 14% of the administered dose is found excreted in the urine as the metabolite, M2. It was noted that less than 1% of the administered dose is excreted unchanged in the urine and thus, renal excretion is not the major elimination pathway.14

Half life

The apparent half-life of tezacaftor is approximately 57.2 hours.4,18

Clearance

The apparent clearance of tezacaftor has been measured at 1.31 L/h for patients in the fed state during a clinical trial.3

Toxicity

The LD50 of an oral dose in rats is >2000 mg/kg.17

Overdose symptoms may include dizziness and diarrhea. There have been no reports to this date of tezacaftor overdose, but the highest dose of 450 mg every 12 hours commonly resulted in reports of dizziness and diarrhea. No antidote exists for treating an overdose with this drug. General supportive measures should be undertaken along with monitoring of vital signs and close monitoring of clinical status.14

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
AbataceptThe metabolism of Tezacaftor can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Tezacaftor.
AcalabrutinibThe metabolism of Tezacaftor can be decreased when combined with Acalabrutinib.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Tezacaftor.
AcetaminophenThe serum concentration of Tezacaftor can be increased when it is combined with Acetaminophen.
AcetyldigoxinTezacaftor may decrease the excretion rate of Acetyldigoxin which could result in a higher serum level.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Tezacaftor.
AdalimumabThe metabolism of Tezacaftor can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Tezacaftor.
AfelimomabThe metabolism of Tezacaftor can be increased when combined with Afelimomab.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, Davies JC, Lekstrom-Himes JA, Wang LT: Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018 Jan 15;197(2):214-224. doi: 10.1164/rccm.201704-0717OC. [PubMed:28930490]
  2. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, Wang LT, Ingenito EP, McKee C, Lu Y, Lekstrom-Himes J, Elborn JS: Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3. [PubMed:29099344]
  3. Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, Nair N, Simard C, Han L, Ingenito EP, McKee C, Lekstrom-Himes J, Davies JC: Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024-2035. doi: 10.1056/NEJMoa1709847. Epub 2017 Nov 3. [PubMed:29099333]
  4. Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J: Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor. Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29. [PubMed:30694595]
  5. Saint-Criq V, Gray MA: Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017 Jan;74(1):93-115. doi: 10.1007/s00018-016-2391-y. Epub 2016 Oct 6. [PubMed:27714410]
  6. Kunzelmann K, Mall M: Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics. Am J Respir Med. 2003;2(4):299-309. [PubMed:14719996]
  7. Fraser-Pitt D, O'Neil D: Cystic fibrosis - a multiorgan protein misfolding disease. Future Sci OA. 2015 Sep 1;1(2):FSO57. doi: 10.4155/fso.15.57. eCollection 2015 Sep. [PubMed:28031875]
  8. Fohner AE, McDonagh EM, Clancy JP, Whirl Carrillo M, Altman RB, Klein TE: PharmGKB summary: ivacaftor pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics. 2017 Jan;27(1):39-42. doi: 10.1097/FPC.0000000000000246. [PubMed:27636560]
  9. Rowe SM, Verkman AS: Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med. 2013 Jul 1;3(7). pii: 3/7/a009761. doi: 10.1101/cshperspect.a009761. [PubMed:23818513]
  10. Cystic fibrosis news [Link]
  11. Vertex news [Link]
  12. Vertex news [Link]
  13. Vertex news [Link]
  14. Symdeko FDA label [Link]
  15. FDA Label: Apadaz [Link]
  16. NIH Medline Tezacaftor/Ivacaftor [Link]
  17. Pharmacology review, FDA [Link]
  18. Monograph, Tezacaftor/Ivacaftor [Link]
  19. FDA Approved Drugs: Trikafta [Link]
External Links
KEGG Drug
D11041
PubChem Compound
46199646
PubChem Substance
347828077
ChemSpider
28637762
BindingDB
281054
ChEMBL
CHEMBL3544914
Wikipedia
Tezacaftor
ATC Codes
R07AX31 — Ivacaftor and tezacaftor
FDA label
Download (459 KB)
MSDS
Download (27.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentCystic Fibrosis (CF)1
1CompletedTreatmentCystic Fibrosis (CF)1
1RecruitingTreatmentCystic Fibrosis (CF)1
1, 2CompletedTreatmentCystic Fibrosis (CF)2
2Active Not RecruitingTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentCystic Fibrosis (CF)7
2RecruitingOtherCystic Fibrosis (CF)1
2RecruitingTreatmentCystic Fibrosis (CF)1
3Active Not RecruitingTreatmentCystic Fibrosis (CF)3
3CompletedTreatmentCystic Fibrosis (CF)11
3Enrolling by InvitationTreatmentCystic Fibrosis (CF)1
3Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
3RecruitingTreatmentCystic Fibrosis (CF)4
3TerminatedTreatmentCystic Fibrosis (CF)1
4RecruitingTreatmentCystic Fibrosis (CF)1
Not AvailableApproved for MarketingNot AvailableCystic Fibrosis (CF)1
Not AvailableAvailableNot AvailableCystic Fibrosis (CF)1
Not AvailableRecruitingNot AvailableCystic Fibrosis (CF)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
KitOral
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8324242No2012-12-042027-04-18Us
US8754224No2014-06-172026-12-28Us
US8410274No2013-04-022026-12-28Us
US7495103No2009-02-242027-05-20Us
US9670163No2017-06-062026-12-28Us
US8415387No2013-04-092027-11-12Us
US9012496No2015-04-212033-07-15Us
US8598181No2013-12-032027-05-01Us
US8629162No2014-01-142025-06-24Us
US8623905No2014-01-072027-05-01Us
US7645789No2010-01-122027-05-01Us
US7776905No2010-08-172027-06-03Us
US9931334No2018-04-032026-12-28Us
US9974781No2018-05-222027-04-09Us
US10022352No2018-07-172027-04-09Us
US10058546No2018-08-282033-07-15Us
US10081621No2018-09-252031-03-25Us
US10206877No2019-02-192035-04-14Us
US10239867No2007-04-092027-04-09Us
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 solubilityInsoluble in waterhttps://www.medkoo.com/products/4790
logP99https://www.medkoo.com/uploads/product/Tezacaftor__VX-661_/safety/MSDS-VX661.pdf
pKa13.99, 0.19https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL3544914/
Predicted Properties
PropertyValueSource
Water Solubility0.0124 mg/mLALOGPS
logP2.97ALOGPS
logP4.03ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)11.54ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area113.18 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity125.53 m3·mol-1ChemAxon
Polarizability51.79 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 n-alkylindoles. These are compounds containing an indole moiety that carries an alkyl chain at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
N-alkylindoles
Direct Parent
N-alkylindoles
Alternative Parents
Indoles / Benzodioxoles / N-arylamides / Substituted pyrroles / Aryl fluorides / Benzenoids / Cyclopropanecarboxylic acids and derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Secondary alcohols
show 9 more
Substituents
N-alkylindole / Indole / Benzodioxole / N-arylamide / Cyclopropanecarboxylic acid or derivatives / Substituted pyrrole / Aryl fluoride / Benzenoid / Aryl halide / Heteroaromatic compound
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Pdz domain binding
Specific Function
Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO...
Gene Name
CFTR
Uniprot ID
P13569
Uniprot Name
Cystic fibrosis transmembrane conductance regulator
Molecular Weight
168139.895 Da
References
  1. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, Davies JC, Lekstrom-Himes JA, Wang LT: Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med. 2018 Jan 15;197(2):214-224. doi: 10.1164/rccm.201704-0717OC. [PubMed:28930490]
  2. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, Wang LT, Ingenito EP, McKee C, Lu Y, Lekstrom-Himes J, Elborn JS: Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3. [PubMed:29099344]
  3. Saint-Criq V, Gray MA: Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017 Jan;74(1):93-115. doi: 10.1007/s00018-016-2391-y. Epub 2016 Oct 6. [PubMed:27714410]
  4. Cystic fibrosis news [Link]
  5. Symdeko FDA label [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J: Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor. Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29. [PubMed:30694595]
  2. Symdeko FDA label [Link]
  3. Monograph, Tezacaftor/Ivacaftor [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J: Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor. Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29. [PubMed:30694595]
  2. Symdeko FDA label [Link]
  3. Monograph, Tezacaftor/Ivacaftor [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J: Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor. Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29. [PubMed:30694595]
  2. Symdeko FDA label [Link]

Drug created on October 20, 2016 14:41 / Updated on November 02, 2019 02:48