Identification

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Name
Ivacaftor
Accession Number
DB08820  (DB05989)
Type
Small Molecule
Groups
Approved
Description

Ivacaftor (also known as Kalydeco or VX-770) is a drug used for the management of Cystic Fibrosis (CF). It is manufactured and distributed by Vertex Pharmaceuticals. It was approved by the Food and Drug Administration on January 31, 201213, and by Health Canada in late 2012.16 Ivacaftor is administered as a monotherapy and also administered in combination with other drugs for the management of CF.14,15,17

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.8

Prior to the development of ivacaftor, management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process or lung function (FEV1). Notably, ivacaftor was the first medication approved for the management of the underlying causes of CF (abnormalities in CFTR protein function) rather than control of symptoms.4

Structure
Thumb
Synonyms
  • Ivacaftor
  • Ivacaftorum
  • N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
External IDs
VX 770 / VX-770 / VX770
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KalydecoGranule50 mg/1OralVertex Pharmaceuticals Incorporated2015-03-23Not applicableUs
KalydecoGranule50 mgOralVertex Pharmaceuticals Incorporated2015-09-14Not applicableCanada
KalydecoTablet, film coated150 mg/1OralVertex Pharmaceuticals Incorporated2012-01-31Not applicableUs
KalydecoTablet150 mgOralVertex Pharmaceuticals Incorporated2012-11-27Not applicableCanada
KalydecoGranule75 mgOralVertex Pharmaceuticals Incorporated2015-09-14Not applicableCanada
KalydecoGranule25 mg/1OralVertex Pharmaceuticals Incorporated2019-04-29Not applicableUs
KalydecoGranule75 mg/1OralVertex Pharmaceuticals Incorporated2015-03-23Not applicableUs
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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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
OrkambiIvacaftor (125 mg) + Lumacaftor (200 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiIvacaftor (188 mg) + Lumacaftor (150 mg)GranuleOralVertex Pharmaceuticals Incorporated2018-12-14Not applicableCanada
OrkambiIvacaftor (125 mg) + Lumacaftor (200 mg)TabletOralVertex Pharmaceuticals Incorporated2016-01-27Not applicableCanada
OrkambiIvacaftor (125 mg/1) + Lumacaftor (100 mg/1)Tablet, film coatedOralVertex Pharmaceuticals Incorporated2016-10-03Not applicableUs
OrkambiIvacaftor (125 mg) + Lumacaftor (100 mg)GranuleOralVertex Pharmaceuticals Incorporated2018-12-14Not applicableCanada
OrkambiIvacaftor (125 mg) + Lumacaftor (200 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiIvacaftor (125 mg/1) + Lumacaftor (200 mg/1)Tablet, film coatedOralVertex Pharmaceuticals Incorporated2015-07-06Not applicableUs
OrkambiIvacaftor (188 mg/1) + Lumacaftor (150 mg/1)GranuleOralVertex Pharmaceuticals Incorporated2018-08-14Not applicableUs
OrkambiIvacaftor (125 mg) + Lumacaftor (200 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiIvacaftor (125 mg) + Lumacaftor (100 mg)TabletOralVertex Pharmaceuticals Incorporated2017-05-03Not applicableCanada
Categories
UNII
1Y740ILL1Z
CAS number
873054-44-5
Weight
Average: 392.4907
Monoisotopic: 392.209992772
Chemical Formula
C24H28N2O3
InChI Key
PURKAOJPTOLRMP-UHFFFAOYSA-N
InChI
InChI=1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
IUPAC Name
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
SMILES
CC(C)(C)C1=CC(=C(O)C=C1NC(=O)C1=CNC2=CC=CC=C2C1=O)C(C)(C)C

Pharmacology

Indication

When used as monotherapy as the product Kalydeco, ivacaftor is indicated for the management of CF in patients age 2 years and older who have a mutation in the CFTR gene that is responsive to ivacaftor potentiation. Ivacaftor received expanded approval in May 2017 for the following 33 CFTR mutations: E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, and G1349D.13,15

When used in combination with the drug lumacaftor as the product Orkambi, ivacaftor is indicated for the management of CF patients age 6 years and older who are shown to be homozygous for the F508del mutation in the CFTR gene.

When used in combination with tezacaftor in the product Symdeko, it is used to manage CF in patients 12 years and older who have at least one mutation in the CFTR gene or patients aged 12 or older who are shown to be homozygous for the F508del mutation.14

When used in combination with tezacaftor and elexacaftor in the product Trikafta, it is indicated for the treatment of cystic fibrosis in patients 12 years of age and older who have at least one F508del mutation in the CFTR gene.18

Associated Conditions
Pharmacodynamics

The use of Ivacaftor has been shown to both improve CF symptoms and modulate underlying disease pathology. This is achieved by potentiating the channel opening probability (or gating) of CFTR protein in patients with impaired gating mechanisms. This is in contrast to Lumacaftor, another CF medication, that functions by preventing misfolding of the CFTR protein and thereby results in increased processing and trafficking of mature protein to the cell surface.

Results from clinical trials indicated that treatment with ivacaftor results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life.15 When combined with tezacaftor, significant improvements in lung function have been observed in clinical studies.14 Ivacaftor was not found to increase the QTc interval in a clinically significant manner.15

Although ivacaftor given alone has not shown any significant improvements in patients with the delta-F508 mutation, it has shown significant improvements (>10% increase in FEV1 from baseline) in lung function for the following mutations: E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, and G1349. 15 This list was expanded by the FDA in May 2017 from 10 to 33 to accommodate more rare mutations.13

It is important to note that this drug may cause an increase in liver transaminases (ALT, AST). Ensure to assess liver transaminases before the initiation of treatment, every 3 months during the first year of administration, followed by every year thereafter.15

Mechanism of action

A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes.7 Ivacaftor as monotherapy has failed to show a benefit for patients with delta-F508 mutations, most likely due to an insufficient amount of protein available at the cell membrane for interaction and potentiation by the drug.10 The next most common mutation, G551D, affecting 4-5% of CF patients worldwide is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered.9 Ivacaftor is indicated for the management of CF in patients with this second type of mutation, as it binds to and potentiates the channel opening ability of CFTR proteins on the cell membrane.9

Ivacaftor exerts its effect by acting as a potentiator of the CFTR protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. 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. Ivacaftor improves CF symptoms and underlying disease pathology by potentiating the channel open probability (or gating) of CFTR protein in patients with impaired CFTR gating mechanisms. The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation 15.

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

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Contraindications

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Blackbox Warnings

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Absorption

Ivacaftor is well absorbed in the gastrointestinal tract.12 Following administration of ivacaftor with fat-containing foods, peak plasma concentrations were reached at 4 hours (Tmax) with a maximum concentration (Cmax) of 768 ng/mL and AUC of 10600 ng * hr/mL. It is recommended that ivacaftor is taken with fat-containing foods as they increase absorption by approximately 2.5- to 4-fold.15

Volume of distribution

After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.15

Protein binding

About 99% of ivacaftor is bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.12,14

Metabolism

Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. From this metabolism, the major formed metabolites are M1 and M6. M1 is considered pharmacologically active even though it just presents approximately one-sixth the effect of the parent compound ivacaftor. On the other hand, M6 is not considered pharmacologically active as it represents less than one-fiftieth of the effect of the parent compound.12,15

Route of elimination

After oral administration, ivacaftor is mainly eliminated in the feces after metabolic conversion and this elimination represents 87.8% of the dose. From the total eliminated dose, the metabolites M1 and M6 account for the majority of the eliminated dose, being 22% for M1 and 43% for M6. Ivacaftor shows negligible urinary excretion as the unchanged drug.12,15

Half life

In a clinical study, the apparent terminal half-life was approximately 12 hours following a single dose of ivacaftor.15 One source mentions the half-life ranges from 12 to 14 hours.12

Clearance

The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.15

Toxicity

LD50 information is not readily available. There have been no reports of overdose with ivacaftor, but when given with tezacaftor, the highest clinical dose lead to diarrhea and dizziness. Provide supportive measures in cases of a suspected overdose. No antidote is available at this time.14

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cystic fibrosis transmembrane conductance regulator---(A;A) / (A;G)A allele (G > A), double homozygoteEffect Directly StudiedPatients who carry this polymorphism in CFTR will respond to ivacaftor therapy.Details

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
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Ivacaftor.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Ivacaftor.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Ivacaftor.
AbataceptThe metabolism of Ivacaftor can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Ivacaftor.
AcalabrutinibThe metabolism of Ivacaftor can be decreased when combined with Acalabrutinib.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Ivacaftor.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Ivacaftor.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Ivacaftor.
AcetyldigoxinIvacaftor may decrease the excretion rate of Acetyldigoxin which could result in a higher serum level.
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

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  • Action
    Action

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Food Interactions
  • Exposure increases 2- to 4- fold when given with a high fat meal. It is recommended that ivacaftor be given this way.

References

General References
  1. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW: Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825. [PubMed:21083385]
  2. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS: A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185. [PubMed:22047557]
  3. Eckford PD, Li C, Ramjeesingh M, Bear CE: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem. 2012 Oct 26;287(44):36639-49. doi: 10.1074/jbc.M112.393637. Epub 2012 Aug 31. [PubMed:22942289]
  4. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P: Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. doi: 10.1073/pnas.0904709106. Epub 2009 Oct 21. [PubMed:19846789]
  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. MacDonald KD, McKenzie KR, Zeitlin PL: Cystic fibrosis transmembrane regulator protein mutations: 'class' opportunity for novel drug innovation. Paediatr Drugs. 2007;9(1):1-10. [PubMed:17291132]
  8. 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]
  9. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F: Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45. doi: 10.1016/j.jcf.2011.12.005. Epub 2012 Jan 30. [PubMed:22293084]
  10. Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, Geller DE: Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012 Sep;142(3):718-724. doi: 10.1378/chest.11-2672. [PubMed:22383668]
  11. Mayer M: Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the 'breakthrough'. Evid Based Med. 2016 Jun;21(3):83-6. doi: 10.1136/ebmed-2015-110325. Epub 2015 Dec 30. [PubMed:26718821]
  12. 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]
  13. FDA Approval Update May 17, 2017 [Link]
  14. Symdeko FDA label [Link]
  15. Kalydeco FDA label [Link]
  16. Cystic Fibrosis, Canada [Link]
  17. FDA label, Orkambi [Link]
  18. FDA Approved Drugs: Trikafta [Link]
External Links
Human Metabolome Database
HMDB0015705
KEGG Drug
D09916
PubChem Compound
16220172
PubChem Substance
175427103
ChemSpider
17347474
BindingDB
50032693
ChEBI
66901
ChEMBL
CHEMBL2010601
PharmGKB
PA165950341
HET
VX7
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ivacaftor
ATC Codes
R07AX31 — Ivacaftor and tezacaftorR07AX02 — IvacaftorR07AX30 — Ivacaftor and lumacaftor
AHFS Codes
  • 48:14.12 — Cystic Fibrosis Transmembrane Conductance Regulator Potentiators
PDB Entries
6o2p
FDA label
Download (239 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
0RecruitingTreatmentChronic Rhinosinusitis (Diagnosis)1
0RecruitingTreatmentCystic Fibrosis (CF)1
1CompletedNot AvailableCystic Fibrosis (CF)1
1CompletedNot AvailableHealthy Volunteers / Hepatic Impairment1
1CompletedBasic ScienceHealthy Volunteers2
1CompletedTreatmentCystic Fibrosis (CF)7
1CompletedTreatmentIn Development for Cystic Fibrosis2
1RecruitingTreatmentCystic Fibrosis (CF)1
1, 2CompletedTreatmentCystic Fibrosis (CF)2
2Active Not RecruitingTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentCystic Fibrosis (CF)14
2CompletedTreatmentPrimary Ciliary Dyskinesia (PCD)1
2Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2RecruitingOtherCystic Fibrosis (CF)1
2RecruitingTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD)1
2RecruitingTreatmentCystic Fibrosis (CF)3
2TerminatedTreatmentCystic Fibrosis (CF)2
3Active Not RecruitingTreatmentCystic Fibrosis (CF)4
3CompletedTreatmentAdvanced Lung Disease / Cystic Fibrosis (CF)1
3CompletedTreatmentCystic Fibrosis (CF)25
3CompletedTreatmentCystic Fibrosis, Homozygous for the F508del CFTR Mutation2
3CompletedTreatmentCystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation1
3Enrolling by InvitationTreatmentCystic Fibrosis (CF)1
3Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
3RecruitingTreatmentCystic Fibrosis (CF)7
3TerminatedTreatmentCystic Fibrosis (CF)2
4Active Not RecruitingBasic ScienceCystic Fibrosis (CF)1
4CompletedOtherCystic Fibrosis (CF)1
4CompletedTreatmentCystic Fibrosis (CF)1
4Not Yet RecruitingTreatmentChronic Bronchitis1
4RecruitingTreatmentCystic Fibrosis (CF)2
4TerminatedTreatmentCystic Fibrosis (CF)1
Not AvailableActive Not RecruitingNot AvailableCystic Fibrosis (CF)2
Not AvailableApproved for MarketingNot AvailableCystic Fibrosis (CF)2
Not AvailableAvailableNot AvailableCystic Fibrosis (CF)1
Not AvailableCompletedNot AvailableCystic Fibrosis (CF)2
Not AvailableCompletedBasic ScienceCystic Fibrosis (CF)1
Not AvailableNot Yet RecruitingOtherCystic Fibrosis (CF) / Homozygous F508del Mutation1
Not AvailableRecruitingNot AvailableCystic Fibrosis (CF)4
Not AvailableRecruitingNot AvailableCystic Fibrosis Homozygous for Phe 508 Del CFTR / Glucose Intolerance or Newly Diagnosis Diabetes1
Not AvailableTerminatedScreeningCystic Fibrosis (CF) / Diabetes Mellitus (DM)1
Not AvailableUnknown StatusScreeningCystic Fibrosis (CF)1
Not AvailableWithdrawnScreeningCystic Fibrosis (CF) / Diabetes Mellitus (DM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral25 mg/1
GranuleOral50 mg/1
GranuleOral50 mg
GranuleOral75 mg
GranuleOral75 mg/1
TabletOral150 mg
Tablet, film coatedOral150 mg/1
GranuleOral
TabletOral
Tablet, film coatedOral
KitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8324242No2012-12-042027-04-18Us
US8354427No2013-01-152026-07-06Us
US8754224No2014-06-172026-12-28Us
US8410274No2013-04-022026-12-28Us
US7495103No2009-02-242027-05-20Us
US8741933No2014-06-032026-11-08Us
US8716338No2014-05-062026-11-08Us
US8846718No2014-09-302028-12-04Us
US8653103No2014-02-182028-12-04Us
US9216969No2015-12-222026-11-08Us
US8507534No2013-08-132030-09-20Us
US8993600No2015-03-312030-12-11Us
US8883206No2014-11-112033-02-27Us
US9670163No2017-06-062026-12-28Us
US9192606No2015-11-242029-09-29Us
US7973038No2011-07-052026-11-08Us
US9150552No2015-10-062028-12-04Us
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
US10076513No2018-09-182028-12-04Us
US10206877No2019-02-192035-04-14Us
US10239867No2007-04-092027-04-09Us
US10272046No2013-02-272033-02-27Us
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
melting point (°C)212-215https://www.trc-canada.com/product-detail/?I940600
boiling point (°C)550.4https://www.lookchem.com/Ivacaftor/
water solubilitylow (<0.05 µg/mL)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5140711/
logP3.13https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2010601/
pKa11.08, 1.5https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2010601/
Predicted Properties
PropertyValueSource
Water Solubility0.002 mg/mLALOGPS
logP5ALOGPS
logP5.76ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)6.57ChemAxon
pKa (Strongest Basic)-0.95ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area78.43 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity118.68 m3·mol-1ChemAxon
Polarizability43.04 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9577
Blood Brain Barrier+0.6561
Caco-2 permeable-0.5608
P-glycoprotein substrateNon-substrate0.5474
P-glycoprotein inhibitor INon-inhibitor0.7677
P-glycoprotein inhibitor IINon-inhibitor0.7609
Renal organic cation transporterNon-inhibitor0.945
CYP450 2C9 substrateNon-substrate0.7374
CYP450 2D6 substrateNon-substrate0.8362
CYP450 3A4 substrateSubstrate0.5686
CYP450 1A2 substrateInhibitor0.5438
CYP450 2C9 inhibitorInhibitor0.6456
CYP450 2D6 inhibitorNon-inhibitor0.9469
CYP450 2C19 inhibitorNon-inhibitor0.6422
CYP450 3A4 inhibitorNon-inhibitor0.8404
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5791
Ames testNon AMES toxic0.8394
CarcinogenicityNon-carcinogens0.8149
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2868 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9961
hERG inhibition (predictor II)Non-inhibitor0.819
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0079-1809000000-c0147e018d786aee606b

Taxonomy

Description
This compound belongs to the class of organic compounds known as aromatic anilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with an aromatic group. They have the general structure RNC(=O)R', where R= benzene, and R = aryl group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Anilides
Direct Parent
Aromatic anilides
Alternative Parents
Quinoline-3-carboxamides / Hydroquinolones / Hydroquinolines / Pyridinecarboxylic acids and derivatives / Phenylpropanes / 1-hydroxy-2-unsubstituted benzenoids / Vinylogous amides / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds
show 5 more
Substituents
Aromatic anilide / Quinoline-3-carboxamide / Dihydroquinolone / Quinoline / Dihydroquinoline / Phenylpropane / Pyridine carboxylic acid or derivatives / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Pyridine
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, phenols, aromatic amide, quinolone (CHEBI:66901)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
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. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F: Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45. doi: 10.1016/j.jcf.2011.12.005. Epub 2012 Jan 30. [PubMed:22293084]
  2. 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]
  3. Kalydeco FDA label [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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. Robertson SM, Luo X, Dubey N, Li C, Chavan AB, Gilmartin GS, Higgins M, Mahnke L: Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein. J Clin Pharmacol. 2015 Jan;55(1):56-62. doi: 10.1002/jcph.377. Epub 2014 Aug 27. [PubMed:25103957]
  2. Guimbellot JS, Acosta EP, Rowe SM: Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer. Pediatr Pulmonol. 2018 May;53(5):E6-E8. doi: 10.1002/ppul.23971. Epub 2018 Feb 28. [PubMed:29488691]
  3. Kalydeco FDA label [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. Robertson SM, Luo X, Dubey N, Li C, Chavan AB, Gilmartin GS, Higgins M, Mahnke L: Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein. J Clin Pharmacol. 2015 Jan;55(1):56-62. doi: 10.1002/jcph.377. Epub 2014 Aug 27. [PubMed:25103957]
  2. Guimbellot JS, Acosta EP, Rowe SM: Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer. Pediatr Pulmonol. 2018 May;53(5):E6-E8. doi: 10.1002/ppul.23971. Epub 2018 Feb 28. [PubMed:29488691]
  3. Kalydeco FDA label [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Carrier
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. Schneider EK, Huang JX, Carbone V, Baker M, Azad MA, Cooper MA, Li J, Velkov T: Drug-drug plasma protein binding interactions of ivacaftor. J Mol Recognit. 2015 Jun;28(6):339-48. doi: 10.1002/jmr.2447. Epub 2015 Feb 24. [PubMed:25707701]
  2. Symdeko FDA label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Carrier
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Schneider EK, Huang JX, Carbone V, Baker M, Azad MA, Cooper MA, Li J, Velkov T: Drug-drug plasma protein binding interactions of ivacaftor. J Mol Recognit. 2015 Jun;28(6):339-48. doi: 10.1002/jmr.2447. Epub 2015 Feb 24. [PubMed:25707701]
  2. Symdeko FDA label [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
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. Robertson SM, Luo X, Dubey N, Li C, Chavan AB, Gilmartin GS, Higgins M, Mahnke L: Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein. J Clin Pharmacol. 2015 Jan;55(1):56-62. doi: 10.1002/jcph.377. Epub 2014 Aug 27. [PubMed:25103957]
  2. McColley SA: A safety evaluation of ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2016 May;15(5):709-15. doi: 10.1517/14740338.2016.1165666. Epub 2016 Apr 7. [PubMed:26968005]

Drug created on February 24, 2012 11:15 / Updated on November 22, 2019 04:20