Elexacaftor

Identification

Summary

Elexacaftor is a small molecule CFTR corrector used in combination with tezacaftor and ivacaftor for the treatment of cystic fibrosis patients with one F508del-CFTR mutation.

Brand Names

Trikafta (100 Mg / 50 Mg / 75 Mg; 150 Mg)

Generic Name

Elexacaftor

DrugBank Accession Number

DB15444

Background

Elexacaftor (previously VX-445) is a small molecule, next-generation corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.³ It received FDA approval in October 2019 in combination with tezacaftor and ivacaftor as the combination product Trikafta^TM.⁶ Elexacaftor is considered a next-generation CFTR corrector as it possesses both a different structure and mechanism as compared to first generation correctors like tezacaftor.³ While dual corrector/potentiator combination therapy has proven useful in the treatment of a subset of CF patients,² their use is typically limited to patients who are homozygous for the F508del-CFTR gene.³ Elexacaftor, along with VX-659, was designed to fill the need for an efficacious CF therapy for patients who are heterozygous for F508del-CFTR and a gene that does not produce protein or produces proteins unresponsive to ivacaftor or tezacaftor.³ The triple combination product Trikafta^TM, manufactured by Vertex Pharmaceuticals, is the first product approved for the treatment of CF in individuals who are either homo- or heterozygous for the F508del-CFTR gene - this represents approximately 70⁴-90%^3,1 of all CF patients.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Elexacaftor (DB15444)

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Weight

Average: 597.66
Monoisotopic: 597.234508266

Chemical Formula

C₂₆H₃₄F₃N₇O₄S

Synonyms

• Elexacaftor

External IDs

• VX-445
• WHO 11180

Pharmacology

Indication

Elexacaftor, in combination with ivacaftor and tezacaftor as the combination product Trikafta^TM, is indicated for the treatment of cystic fibrosis (CF) in patients 12 years of age and older who have at least one F508del mutation in the CTFR gene.⁶

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Associated Conditions

• Cystic Fibrosis (CF)

Contraindications & Blackbox Warnings

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Pharmacodynamics

As a CFTR corrector, elexacaftor works to increase the amount of mature CFTR proteins present on the surface of cells.⁶ When used in combination with CFTR potentiators, which enhance the function of cell-surface CFTR proteins, drugs like elexacaftor help to improve a variety of multi-organ cystic fibrosis symptoms, including lung function, nutritional status, and overall quality of life.³ Trikafta^TM, the triple combination product containing elexacaftor, may cause elevations in liver transaminases. Liver function testing should be conducted prior to beginning Trikafta, every 3 months for the first year of treatment, and annually thereafter.⁶

Mechanism of action

Cystic fibrosis (CF) is the result of a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.⁴ The CFTR proteins produced by this gene are transmembrane ion channels that move sodium and chloride across cell membranes - water follows the flow of chloride ions to the cell surface, which consequently helps to hydrate the surface of the cell and thin the secretions (i.e. mucous) around the cell.⁴ Mutations in the CFTR gene produce CFTR proteins of insufficient quantity and/or function, leading to defective ion transport and a build-up of thick mucous throughout the body that causes multi-organ disease involving the pulmonary, gastrointestinal, and pancreatic systems (amongst others). The most common CFTR mutation, the F508del mutation, is estimated to account for 70⁴ to 90%^3,1 of all CFTR mutations and results in severe processing and trafficking defects of the CFTR protein.²

Elexacaftor is a CFTR corrector that modulates CFTR proteins to facilitate trafficking to the cell surface for incorporation into the cell membrane.⁶ The end result is an increase in the number of mature CFTR proteins present at the cell surface and, therefore, improved ion transport and CF symptomatology. Elexacaftor is used in combination with tezacaftor, another CFTR corrector with a different mechanism of action, and ivacaftor, a CFTR potentiator that improves the function of CFTR proteins on the cell surface - this multi-faceted, triple-drug approach confers a synergistic effect beyond that seen in typical corrector/potentiator dual therapy regimens.^6,3

Target	Actions	Organism
ACystic fibrosis transmembrane conductance regulator	modulator	Humans

Absorption

The absolute oral bioavailability of elexacaftor is approximately 80%. The steady-state AUC_0-24h and C_max following once daily dosing with elexacaftor 200mg are 162 mcg∙h/mL and 8.7 mcg/mL, respectively, and the median T_max is 6 hours.⁶ The AUC of elexacaftor is increased 1.9-2.5-fold following a moderate-fat meal - for this reason, it is recommended to give Trikafta^TM with fat-containing food.⁶

Volume of distribution

The apparent volume of distribution of elexacaftor is 53.7 L.⁶

Protein binding

Elexacaftor is >99% protein bound in plasma, primarily to albumin.⁶

Metabolism

The metabolism of elexacaftor is extensive and primarily catalyzed via CYP3A4/5.⁶ Its main active metabolite, M23-ELX, carries a similar potency as the parent drug.⁶ The precise metabolic pathway of elexacaftor has not yet been elucidated in published research.

Route of elimination

Approximately 87.3% of an administered radio-labeled dose of elexacaftor was found in the feces, mostly as metabolites, while only 0.23% of that same dose was found excreted in the urine.⁶

Half-life

The mean terminal half-life of elexacaftor is approximately 24.7 hours.⁶

Clearance

The mean apparent clearance of elexacaftor is 1.18 L/h.⁶

Adverse Effects

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Toxicity

As elexacaftor is currently only available in the combination product Trikafta^TM (ivacaftor/tezacaftor/elexacaftor), data regarding overdose of elexacaftor on its own is unavailable.⁶ Treatment of Trikafta^TM overdose should consist of general supportive and symptomatic treatment, including monitoring of vital signs and close observation of the affected patient.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Elexacaftor can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Elexacaftor can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Elexacaftor.
Abiraterone	The serum concentration of Elexacaftor can be increased when it is combined with Abiraterone.
Acalabrutinib	The metabolism of Elexacaftor can be decreased when combined with Acalabrutinib.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Elexacaftor.
Acetaminophen	The metabolism of Elexacaftor can be increased when combined with Acetaminophen.
Acetazolamide	The metabolism of Elexacaftor can be decreased when combined with Acetazolamide.
Adalimumab	The metabolism of Elexacaftor can be increased when combined with Adalimumab.
Albendazole	The metabolism of Elexacaftor can be decreased when combined with Albendazole.

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Food Interactions

• Avoid grapefruit products. Co-administration of grapefruit can inhibit elexacaftor metabolism and increase serum concentrations.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of elexacaftor.
• Take with a high fat meal. Examples include food prepared with eggs, cheeses, nuts, oils, and butter.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Kaftrio	Elexacaftor (100 mg) + Ivacaftor (75 mg) + Tezacaftor (50 mg)	Tablet, film coated	Oral	Vertex Pharmaceuticals (Ireland) Limited	2020-12-15	Not applicable
Trikafta	Elexacaftor (100 mg/1) + Ivacaftor (75 mg/1) + Ivacaftor (150 mg/1) + Tezacaftor (50 mg/1)	Tablet	Oral	Vertex Pharmaceuticals Incorporated	2019-10-21	Not applicable

Categories

Drug Categories

• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates (strength unknown)
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Membrane Transport Modulators
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

RRN67GMB0V

CAS number

2216712-66-0

InChI Key

MVRHVFSOIWFBTE-INIZCTEOSA-N

InChI

InChI=1S/C26H34F3N7O4S/c1-16-12-25(5,6)35(13-16)22-18(23(37)33-41(38,39)19-14-34(7)31-17(19)2)8-9-20(30-22)36-11-10-21(32-36)40-15-24(3,4)26(27,28)29/h8-11,14,16H,12-13,15H2,1-7H3,(H,33,37)/t16-/m0/s1

IUPAC Name

N-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

SMILES

C[C@@H]1CN(C2=NC(=CC=C2C(=O)NS(=O)(=O)C2=CN(C)N=C2C)N2C=CC(OCC(C)(C)C(F)(F)F)=N2)C(C)(C)C1

References

General References

1. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL: VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1612-1620. doi: 10.1056/NEJMoa1807120. Epub 2018 Oct 18. [Article]
2. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL, Tullis E, Uluer A, McKee CM, Robertson S, Shilling RA, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Rowe SM: VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1599-1611. doi: 10.1056/NEJMoa1807119. Epub 2018 Oct 18. [Article]
3. Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, Marigowda G, McKee CM, Waltz D, Moskowitz SM, Savage J, Xuan F, Rowe SM: Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res. 2019 Jun 17;5(2). pii: 00082-2019. doi: 10.1183/23120541.00082-2019. eCollection 2019 Apr. [Article]
4. Brown SD, White R, Tobin P: Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment. JAAPA. 2017 May;30(5):23-27. doi: 10.1097/01.JAA.0000515540.36581.92. [Article]
5. FDA News Release: Trikafta Approval [Link]
6. FDA Approved Drug Products: Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor tablets) [Link]

External Links

ChemSpider

75531299

RxNav

2256951

ChEMBL

CHEMBL4298128

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Not Yet Recruiting	Other	Drug Drug Interaction (DDI)	1
4	Recruiting	Treatment	Cystic Fibrosis (CF)	1
3	Active Not Recruiting	Treatment	Cystic Fibrosis (CF)	6
3	Completed	Treatment	Cystic Fibrosis (CF)	5
3	Enrolling by Invitation	Treatment	Cystic Fibrosis (CF)	1
3	Recruiting	Treatment	Cystic Fibrosis (CF)	2
2	Recruiting	Treatment	Cystic Fibrosis (CF)	1
1, 2	Completed	Treatment	Cystic Fibrosis (CF)	1
Not Available	Approved for Marketing	Not Available	Cystic Fibrosis (CF)	1
Not Available	Available	Not Available	Cystic Fibrosis (CF)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral
Tablet	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8324242	No	2012-12-04	2027-04-18
US8354427	No	2013-01-15	2026-07-06
US8754224	No	2014-06-17	2026-12-28
US8410274	No	2013-04-02	2026-12-28
US7495103	No	2009-02-24	2027-05-20
US9670163	No	2017-06-06	2026-12-28
US8415387	No	2013-04-09	2027-11-12
US9012496	No	2015-04-21	2033-07-15
US8598181	No	2013-12-03	2027-05-01
US8629162	No	2014-01-14	2025-06-24
US8623905	No	2014-01-07	2027-05-01
US7645789	No	2010-01-12	2027-05-01
US7776905	No	2010-08-17	2027-06-03
US9931334	No	2018-04-03	2026-12-28
US9974781	No	2018-05-22	2027-04-09
US10022352	No	2018-07-17	2027-04-09
US10081621	No	2018-09-25	2031-03-25
US10239867	No	2019-03-26	2027-04-09
US10646481	No	2009-08-13	2029-08-13
US10758534	No	2015-10-06	2035-10-06
US10793547	No	2017-12-08	2037-12-08

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	<1mg/mL	Trikafta FDA Label

Predicted Properties

Property	Value	Source
Water Solubility	0.0192 mg/mL	ALOGPS
logP	4.46	ALOGPS
logP	5.04	ChemAxon
logS	-4.5	ALOGPS
pKa (Strongest Acidic)	4.1	ChemAxon
pKa (Strongest Basic)	2.09	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	8	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	124.24 Å2	ChemAxon
Rotatable Bond Count	8	ChemAxon
Refractivity	160.13 m3·mol-1	ChemAxon
Polarizability	60.59 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Cystic fibrosis transmembrane conductance regulator

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Modulator

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. FDA Approved Drug Products: Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor tablets) [Link]

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Drug created on May 20, 2019 15:32 / Updated on February 21, 2021 18:55