U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C24H28N2O3
Molecular Weight 392.4916
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of IVACAFTOR

SMILES

CC(C)(C)c1cc(c(cc1N=C(c2c[nH]c3ccccc3c2=O)O)O)C(C)(C)C

InChI

InChIKey=PURKAOJPTOLRMP-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C24H28N2O3
Molecular Weight 392.4916
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Ivacaftor (trade names KALYDECO® (ivacaftor) and ORKAMBI® (lumacaftor/ivacaftor)) is a cystic fibrosis transmembrane conductance regulator potentiator indicated for the treatment of cystic fibrosis in patients age 6 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. One such defect G551D is characterized by a dysfunctional CFTR protein on the cell surface. Although the defective protein is trafficked to the correct area, the epithelial cell surface, while there it cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open. Ivacaftor regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus.

Originator

Curator's Comment:: Vertex initiated its CF research program in 1998 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. KALYDECO® (ivacaftor) and ORKAMBI® (lumacaftor/ivacaftor) were discovered by Vertex as part of this collaboration.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
KALYDECO

Approved Use

KALYDECO is indicated for the treatment of CF in patients age 6 years and older who have an R117H mutation in the CFTR gene

Launch Date

1327968000000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
2212 ng/mL
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVACAFTOR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
44916 ng × h/mL
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVACAFTOR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
15 h
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVACAFTOR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
Doses

Doses

DosePopulationAdverse events​
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2 years
Health Status: unhealthy
Age Group: 2 years
Sex: M
Sources:
Disc. AE: ALT increased...
AEs leading to
discontinuation/dose reduction:
ALT increased (1 patient)
Sources:
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Disc. AE: Elevated liver enzymes, Croup...
AEs leading to
discontinuation/dose reduction:
Elevated liver enzymes (2 patients)
Croup (1 patient)
Sepsis (1 patient)
Sources:
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Disc. AE: Elevated liver enzymes, Vomiting...
AEs leading to
discontinuation/dose reduction:
Elevated liver enzymes (1 patient)
Vomiting (2 patients)
Gastroenteritis (1 patient)
Retching (1 patient)
Rash (1 patient)
Cough increased (1 patient)
Sources:
450 mg 2 times / day multiple, oral
Overdose
Dose: 450 mg, 2 times / day
Route: oral
Route: multiple
Dose: 450 mg, 2 times / day
Sources:
healthy, adult
Other AEs: Dizziness, Diarrhea...
AEs

AEs

AESignificanceDosePopulation
ALT increased 1 patient
Disc. AE
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2 years
Health Status: unhealthy
Age Group: 2 years
Sex: M
Sources:
Croup 1 patient
Disc. AE
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Sepsis 1 patient
Disc. AE
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Elevated liver enzymes 2 patients
Disc. AE
50 mg 2 times / day steady, oral
Recommended
Dose: 50 mg, 2 times / day
Route: oral
Route: steady
Dose: 50 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Cough increased 1 patient
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Elevated liver enzymes 1 patient
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Gastroenteritis 1 patient
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Rash 1 patient
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Retching 1 patient
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Vomiting 2 patients
Disc. AE
75 mg 2 times / day steady, oral
Recommended
Dose: 75 mg, 2 times / day
Route: oral
Route: steady
Dose: 75 mg, 2 times / day
Sources:
unhealthy, 2-6 years
Health Status: unhealthy
Age Group: 2-6 years
Sources:
Diarrhea
450 mg 2 times / day multiple, oral
Overdose
Dose: 450 mg, 2 times / day
Route: oral
Route: multiple
Dose: 450 mg, 2 times / day
Sources:
healthy, adult
Dizziness
450 mg 2 times / day multiple, oral
Overdose
Dose: 450 mg, 2 times / day
Route: oral
Route: multiple
Dose: 450 mg, 2 times / day
Sources:
healthy, adult
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
no
weak [IC50 11 uM]
weak [IC50 3.8 uM]
weak [IC50 41 uM]
weak (co-administration study)
Comment: ivacaftor increased midazolam exposure 1.5x, cmax 1.38x, auc 1.54x
Page: 3
yes [IC50 0.17 uM]
yes [IC50 3.4 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: ketoconazole increased ivacaftor exposure by 8.5x; fluconazole increased ivacaftor exposure by 3x; rifampin decreased ivacaftor exposure by 9x
Page: 3
no
no
no (co-administration study)
Comment: rosiglitazone had no effect on cmax and auc of ivacaftor
Page: 6
no
no (co-administration study)
Comment: desipramine had no effect on cmax and auc of ivacaftor
Page: 6
Tox targets
PubMed

PubMed

TitleDatePubMed
Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
2009 Nov 3
Targeting the basic defect in cystic fibrosis.
2010 Nov 18
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
2010 Nov 18
Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant.
2011 Jul 15
Cystic fibrosis transmembrane regulator potentiators as promising cystic fibrosis therapies.
2011 Mar
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
2011 Nov 3
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.
2012 Oct 26
Patents

Sample Use Guides

Adults and pediatric patients age 6 years and older: one 150 mg tablet taken orally every 12 hours with fat-containing food. Reduce dose in patients with moderate and severe hepatic impairment. Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.
Route of Administration: Oral
10 uM ivacaftor increased the channel open probability of all CFTR gating mutations tested, reaching levels equivalent to 30% to 118% of normal CFTR.
Substance Class Chemical
Created
by admin
on Sat Jun 26 05:26:17 UTC 2021
Edited
by admin
on Sat Jun 26 05:26:17 UTC 2021
Record UNII
1Y740ILL1Z
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
IVACAFTOR
DASH   INN   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
N-(2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYL)-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDE
Systematic Name English
IVACAFTOR [INN]
Common Name English
ORKAMBI COMPONENT IVACAFTOR
Brand Name English
TRIKAFTA COMPONENT IVACAFTOR
Brand Name English
IVACAFTOR [WHO-DD]
Common Name English
IVACAFTOR COMPONENT OF ORKAMBI
Brand Name English
IVACAFTOR [VANDF]
Common Name English
IVACAFTOR [ORANGE BOOK]
Common Name English
IVACAFTOR [MI]
Common Name English
3-QUINOLINECARBOXAMIDE, N-(2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYL)-1,4-DIHYDRO-4-OXO-
Systematic Name English
IVACAFTOR [USAN]
Common Name English
VX-770
Code English
KALYDECO
Brand Name English
SYMKEVI COMPONENT IVACAFTOR
Brand Name English
IVACAFTOR COMPONENT OF TRIKAFTA
Brand Name English
Classification Tree Code System Code
WHO-VATC QR07AX02
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
FDA ORPHAN DRUG 228306
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
LIVERTOX 526
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
EMA ASSESSMENT REPORTS ORKAMBI (AUTHORIZED: CYSTIC FIBROSIS)
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
FDA ORPHAN DRUG 577517
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
FDA ORPHAN DRUG 647618
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
EU-Orphan Drug EU/3/18/2116
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
EMA ASSESSMENT REPORTS KALYDECO (AUTHORIZED: CYSTIC FIBROSIS)
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
FDA ORPHAN DRUG 434814
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
NDF-RT N0000184146
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
WHO-ATC R07AX30
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
FDA ORPHAN DRUG 638618
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
WHO-ATC R07AX02
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
WHO-ATC R07AX31
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
Code System Code Type Description
EVMPD
SUB33103
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
IUPHAR
4342
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
LACTMED
Lumacaftor and Ivacaftor
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
NDF-RT
N0000184145
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY Chloride Channel Activation Potentiators [MoA]
INN
9263
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
DRUG CENTRAL
4228
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
RXCUI
1243041
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY RxNorm
FDA UNII
1Y740ILL1Z
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
PUBCHEM
16220172
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
NDF-RT
N0000185504
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY Cytochrome P450 2C9 Inhibitors [MoA]
NDF-RT
N0000190114
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY Cytochrome P450 3A Inhibitors [MoA]
ChEMBL
CHEMBL2010601
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
LACTMED
Elexacaftor, Tezacaftor and Ivacaftor
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
DRUG BANK
DB08820
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
CAS
873054-44-5
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
NDF-RT
N0000185503
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY P-Glycoprotein Inhibitors [MoA]
NCI_THESAURUS
C166523
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
LACTMED
Tezacaftor and Ivacaftor
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
EPA CompTox
873054-44-5
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
WIKIPEDIA
IVACAFTOR
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
NDF-RT
N0000182141
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY Cytochrome P450 3A4 Inhibitors [MoA]
MERCK INDEX
M6565
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY Merck Index
LACTMED
Ivacaftor
Created by admin on Sat Jun 26 05:26:17 UTC 2021 , Edited by admin on Sat Jun 26 05:26:17 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A.
MAJOR
METABOLIC ENZYME -> SUBSTRATE
BINDER->LIGAND
Ivacaftor is approximately 99% bound to plasma proteins, primarily to albumin, and also to alpha 1-acid glycoprotein and human gamma-globulin.
BINDING
EXCRETED UNCHANGED
There was negligible urinary excretion of ivacaftor as unchanged drug.
INHIBITOR OF AGGREGATION->TARGET
Related Record Type Details
METABOLITE INACTIVE -> PARENT
MAJOR
METABOLITE INACTIVE -> PARENT
METABOLITE INACTIVE -> PARENT
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC
Tmax PHARMACOKINETIC ORAL ADMINISTRATION