You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameIvacaftor
Accession NumberDB08820
TypeSmall Molecule
GroupsApproved
Description

Ivacaftor (also known as Kalydeco or VX-770) is a drug for the treatment of cystic fibrosis, developed by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation. FDA approved on January 31, 2012.

Structure
Thumb
Synonyms
SynonymLanguageCode
IvacaftorumNot AvailableNot Available
KalydecoNot AvailableNot Available
VX-770Not AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kalydecotablet, film coated150 mgoralVertex Pharmaceuticals Incorporated2012-01-31Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Kalydecotablet150 mgoralVertex Pharmaceuticals (Canada) IncorporatedNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number873054-44-5
WeightAverage: 392.4907
Monoisotopic: 392.209992772
Chemical FormulaC24H28N2O3
InChI KeyPURKAOJPTOLRMP-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinoline-3-carboxamides. These are quinolines in which the quinoline ring system is substituted by one carboxamide group at the 3-position.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassQuinolines and derivatives
Sub ClassQuinoline carboxamides
Direct ParentQuinoline-3-carboxamides
Alternative Parents
Substituents
  • Quinoline-3-carboxamide
  • Dihydroquinolone
  • N-arylamide
  • Dihydroquinoline
  • Pyridine carboxylic acid or derivatives
  • Phenylpropane
  • Phenol
  • Benzenoid
  • Pyridine
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous amide
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.
PharmacodynamicsIvacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR). In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.
Mechanism of actionCystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator, which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. The defect, which is caused by a mutation in the individual's DNA, can be in any of several locations along the protein, each of which interferes with a different function of the protein. One mutation, G551D, lets the CFTR protein reach the epithelial cell surface, but doesn't let it transport chloride through the ion channel. Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the G551D-CFTR protein.
AbsorptionThe pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF. When given a single oral dose of 150 mg to healthy subjects, the parameters were as follows: Tmax = 4 hours; Cmax = 768 ng/mL; AUC = 10600 ng*hr/mL; Time to steady state, 12 hour dosing = 3-5 days Following repeated doses for ivacaftor, accumulation occurs. When given with a fatty meal, exposure increases 2-4 fold.
Volume of distribution

The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of Ivacaftor in the fed state was similar for healthy subjects and patients with CF. 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.

Protein bindingIvacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.
Metabolism

Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Route of eliminationFollowing oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent.
Half life12 hours following a single dose
Clearance

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

ToxicityThere have been no reports of overdose with Ivacaftor. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Cystic fibrosis transmembrane conductance regulator
Gene symbol: CFTR
UniProt: P13569
rs75527207 Not AvailableA allele (G > A)Cystic Fibrosis patients with the A allele will response to ivacaftor23757359
Cystic fibrosis transmembrane conductance regulator
Gene symbol: CFTR
UniProt: P13569
rs75527207 Not AvailableA allele (G > A)Cystic Fibrosis patients with the A allele will response to ivacaftor23891399
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateInhibitor0.6456
CYP450 2D6 substrateNon-inhibitor0.9469
CYP450 2C19 substrateNon-inhibitor0.6422
CYP450 3A4 substrateNon-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
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral150 mg
Tablet, film coatedoral150 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States74951032012-01-312027-05-20
United States83242422012-01-312027-04-18
United States84102742012-01-312026-12-28
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityInsoluble (<0.05 µg/mL)FDA label
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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  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. Pubmed
  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. Pubmed
External Links
ATC CodesR07AX02
AHFS Codes
  • 48:92
PDB EntriesNot Available
FDA labelDownload (239 KB)
MSDSDownload (353 KB)
Interactions
Drug Interactions
Drug
AlvimopanDecreases levels by P-glycoprotein (MDR-1) efflux transporter. Can significantly increase systemic exposure to P-glycoprotein substrates.
BendamustineIncreases levels of bendamustine by P-glycoprotein (MDR-1) efflux transporter.
CarbamazepineStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
ClarithromycinStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
ErythromycinModerate CYP3A4 inhibitors may increase levels of ivacaftor. Consider dose reduction.
EtravirineIvacaftor, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid this combination.
FluconazoleModerate CYP3A4 inhibitors may increase levels of ivacaftor. Consider dose reduction.
ItraconazoleStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
KetoconazoleStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
PazopanibInhibits p-glycoprotein and affects heptatic metabolism via CYP3A4 therefore increases levels of pazopanib. Consider alternate therapy.
PhenobarbitalStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
PhenytoinStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
PosaconazoleStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
RifabutinStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
RifampicinStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
St. John's WortStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
TelithromycinStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
TofacitinibIvacaftor, when used in combination with tofacitinib, may increase tofaciitinib concentrations, It is recommended to monitor therapy for signs of toxicity or worsened side effects.
VismodegibP-glycoprotein inhibitors may increase the chance of adverse drug reactions. Consider using alternative therapy.
VoriconazoleStrong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Food Interactions
  • Exposure increases 2- to 4- fold when given with a high fat meal. It is recommended that ivacaftor be given this way.

Targets

1. Cystic fibrosis transmembrane conductance regulator

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Cystic fibrosis transmembrane conductance regulator P13569 Details

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 Jan 30. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA Label

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

2. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. FDA label

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. FDA Label

Comments
comments powered by Disqus
Drug created on February 24, 2012 11:15 / Updated on September 16, 2013 18:11