Identification

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Name
Elexacaftor
Accession Number
DB15444
Type
Small Molecule
Groups
Approved, Investigational
Description

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 TrikaftaTM.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 TrikaftaTM, 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.

Structure
Thumb
Synonyms
  • Elexacaftor
External IDs
VX-445 / WHO 11180
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
TrikaftaElexacaftor (100 mg/1) + Ivacaftor (75 mg/1) + Ivacaftor (150 mg/1) + Tezacaftor (50 mg/1)OralVertex Pharmaceuticals Incorporated2019-10-21Not applicableUs
Categories
UNII
RRN67GMB0V
CAS number
2216712-66-0
Weight
Average: 597.66
Monoisotopic: 597.234508266
Chemical Formula
C26H34F3N7O4S
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

Pharmacology

Indication

Elexacaftor, in combination with ivacaftor and tezacaftor as the combination product TrikaftaTM, 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

Associated Conditions
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 TrikaftaTM, 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

TargetActionsOrganism
ACystic fibrosis transmembrane conductance regulator
modulator
Humans
Additional Data Available
Adverse Effects

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Contraindications

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Blackbox Warnings

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Absorption

The absolute oral bioavailability of elexacaftor is approximately 80%. The steady-state AUC0-24h and Cmax following once daily dosing with elexacaftor 200mg are 162 mcg∙h/mL and 8.7 mcg/mL, respectively, and the median Tmax 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 TrikaftaTM 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

Toxicity

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

Affected organisms
Not Available
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
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Elexacaftor.
6-Deoxyerythronolide BThe metabolism of Elexacaftor can be decreased when combined with 6-Deoxyerythronolide B.
7-ethyl-10-hydroxycamptothecinThe metabolism of Elexacaftor can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of Elexacaftor can be decreased when combined with 9-aminocamptothecin.
AbataceptThe metabolism of Elexacaftor can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Elexacaftor can be decreased when combined with Acalabrutinib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Elexacaftor.
AcetaminophenThe metabolism of Elexacaftor can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Elexacaftor can be decreased when combined with Acetazolamide.
AdalimumabThe metabolism of Elexacaftor can be increased when combined with Adalimumab.
Additional Data Available
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Food Interactions
Not Available

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. [PubMed:30334692]
  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. [PubMed:30334693]
  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. [PubMed:31218221]
  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. [PubMed:28441669]
  5. FDA News Release: Trikafta Approval [Link]
  6. FDA Approved Drugs: Trikafta [Link]
External Links
ChemSpider
75531299

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentCystic Fibrosis (CF)1
3Active Not RecruitingTreatmentCystic Fibrosis (CF)1
3CompletedTreatmentCystic Fibrosis (CF)2
3Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
3RecruitingTreatmentCystic Fibrosis (CF)4
Not AvailableApproved for MarketingNot AvailableCystic Fibrosis (CF)1
Not AvailableRecruitingNot AvailableCystic Fibrosis (CF)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1mg/mLTrikafta FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0192 mg/mLALOGPS
logP4.46ALOGPS
logP5.04ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)4.1ChemAxon
pKa (Strongest Basic)2.09ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area124.24 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity160.13 m3·mol-1ChemAxon
Polarizability60.59 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

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 Drugs: Trikafta [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drugs: Trikafta [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
References
  1. FDA Approved Drugs: Trikafta [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drugs: Trikafta [Link]
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. FDA Approved Drugs: Trikafta [Link]

Drug created on May 20, 2019 09:32 / Updated on November 02, 2019 03:33