Identification

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

Tezacaftor is a small molecule that can be used as a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) gene function.[4] It was developed by Vertex Pharmaceuticals and FDA approved in combination with ivacaftor; a CFTR potentiator that allows the proteins at the cell surface to open longer and improve nutrient transport.[5] The approval was done on February 12, 2018, to be used under prescription.

Structure
Thumb
Synonyms
Not Available
External IDs
VX 661 / VX-661 / VX661
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
SymdekoTezacaftor (100 mg/1) + Ivacaftor (150 mg/1) + Ivacaftor (150 mg/1)KitVertex Pharmaceuticals Incorporated2018-02-13Not 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, in combination with ivacaftor, is indicated for the treatment of cystic fibrosis in people aged 12 years or older who have two copies of the F508del mutation or at least one mutation in the CFTR gene that is responsive to this treatment based on clinical evidence.[6]

Cystic fibrosis is a rare, life-shortening disease caused by a defective or missing CFTR protein. This modification in the protein is caused by a mutation in the CFTR gene. The affected people carry two inherited defective copies of the CFTR gene. There are approximately 2000 known mutations in the CFTR gene. The presence of a defective or missing protein results in poor flow of salt and water into and out of the cell. This condition will cause the buildup of abnormally thick, sticky mucus in the lungs that will later potentially cause chronic lung infections and lung damage. In the patients with the F508del mutation, the CFTR protein is not processed or folded normally within the cell and thus, it does not reach the cell surface.[7]

Pharmacodynamics

Some clinical studies have shown a significant decrease in sweat chloride and an increase in the forced expiratory volume.[1] The phase 3 clinical studies have shown that a significant increase in forced expiratory volume was attained at 4 and 8 weeks after the beginning of the treatment. Tezacaftor significantly improved the respiratory domain as seen by the cystic fibrosis questionnaire-revised.[4] Studies have also reported that tezacaftor does not provoke QT prolongation to any clinically relevant extent.[2]

Mechanism of action

Normally, the transport of charged ions across cell membranes is achieved through the cystic fibrosis transmembrane regulator protein. This protein serves as a channel and allows passage of charged ions such as chlorine or sodium. This process is also important for the movement of water in the tissues and for the creation of a thin mucus that can lubricate some of the organs and body tissues, including the lungs. In the F508del mutation of CFTR, one amino acid is deleted in the position 508 and thus the channel function is compromised and thick mucus is produced.[4]

Tezacaftor is able to restore the CFTR gene function by moving the protein into the correct position on the cell surface. This process is performed via facilitation of cellular processing and trafficking.[4]

The use of ivacaftor is related to its potential to provoke the open channel state which will increase the chloride transport.[7]

TargetActionsOrganism
ACystic fibrosis transmembrane conductance regulator
activator
Human
Absorption

After administration of tezacaftor and ivacaftor, the plasma concentration of both compounds reached steady-state within 8 days for tezacaftor and 2-5 days for ivacaftor. When reached steady state, the accumulation of both will be 1.5 for tezacaftor and 2.2 for ivacaftor. The Cmax, tmax and AUC of tezacaftor, when administered with ivacaftor, is 5.95 mcg/ml, 2-6 h and 84.5 mcg.h/ml respectively.[3] Exposure of tezacaftor/ivacaftor is 3 times higher exposure when administered with high-fat containing food.[Label]

Volume of distribution

The apparent volume of distribution of tezacaftor is 271 L.[Label]

Protein binding

Tezacaftor is approximately bound in a proportion of 99% of the administered dose. From the bound state, most of the dose is bound to albumin.[Label]

Metabolism

Tezacaftor is metabolized extensively in humans by the action of CYP3A4 and CYP3A5. There are three main circulating metabolites named M1, M2 and M5. From the metabolites, M1 is an active metabolite with a similar potency than tezacaftor, M2 is less pharmacologically active and M5 is an inactive metabolite. There is an additional circulating metabolite, named M3, that corresponds to the glucuronide form of tezacaftor.[Label]

Route of elimination

Following oral administration, the majority of tezacaftor dose reaching to even 72% of the administered dose is excreted by the feces either unchanged or as the metabolite M2 and about 14% of the administered dose is recovered in urine as the metabolite M2. These percentages correspond to a 86% of the recovered dose after 21 days of administration. 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.[Label]

Half life

The apparent half-life of tezafacor is approximately 15 hours.[3]

Clearance

The apparent clearance of tezacaftor is registered to be 1.31 L/h.[3]

Toxicity

Tezacaftor, administered individually, does not present evidence of tumorigenicity, genotoxicity or effects in male or female fertility or early embryonic development.[Label]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Tezacaftor can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Tezacaftor.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Tezacaftor.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Tezacaftor.
5-androstenedioneThe metabolism of Tezacaftor can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Tezacaftor can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Tezacaftor.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Tezacaftor.
AbirateroneThe metabolism of Tezacaftor can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Tezacaftor can be decreased when combined with Acalabrutinib.
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. Cystic fibrosis news [Link]
  5. Vertex news [Link]
  6. Vertex news [Link]
  7. Vertex news [Link]
External Links
KEGG Drug
D11041
PubChem Compound
46199646
PubChem Substance
347828077
ChemSpider
28637762
ChEMBL
CHEMBL3544914
Wikipedia
Tezacaftor
FDA label
Download (459 KB)
MSDS
Download (27.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
1CompletedTreatmentCystic Fibrosis (CF)1
1RecruitingTreatmentCystic Fibrosis (CF)1
1, 2CompletedTreatmentCystic Fibrosis (CF)1
2Active Not RecruitingTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentCystic Fibrosis (CF)6
3Active Not RecruitingTreatmentCystic Fibrosis (CF)2
3CompletedTreatmentCystic Fibrosis (CF)3
3Enrolling by InvitationTreatmentCystic Fibrosis (CF)3
3Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
3RecruitingTreatmentCystic Fibrosis (CF)5
Not AvailableApproved for MarketingNot AvailableCystic Fibrosis (CF)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8324242No2007-04-182027-04-18Us
US8754224No2006-12-282026-12-28Us
US8410274No2006-12-282026-12-28Us
US7495103No2007-05-202027-05-20Us
US9670163No2006-12-282026-12-28Us
US8415387No2007-11-122027-11-12Us
US9012496No2013-07-152033-07-15Us
US8598181No2007-05-012027-05-01Us
US8629162No2005-06-242025-06-24Us
US8623905No2007-05-012027-05-01Us
US7645789No2007-05-012027-05-01Us
US7776905No2007-06-032027-06-03Us
US9931334No2006-12-282026-12-28Us
US9974781No2007-04-092027-04-09Us
US10022352No2007-04-092027-04-09Us
US10058546No2013-07-152033-07-15Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)610.8ºC at 760 mmHgChemyclass
water solubilityInsoluble'MSDS'
logP99'MSDS'
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
Human
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. Cystic fibrosis news [Link]

Enzymes

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
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

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Drug created on October 20, 2016 14:41 / Updated on November 02, 2018 07:14