General
Preferred name
IVACAFTOR
Synonyms
Ivacaftor (hydrate) ()
Ivacaftor (benzenesulfonate) ()
VX-770 hydrate ()
VX-770 benzenesulfonate ()
VX-770 ()
Ivacaftor (VX-770) ()
VX-770 (Ivacaftor) ()
VX 770 ()
Deutivacaftor ()
Ivacaftor hydrate ()
Kalydeco ()
CTP-656 ()
D9-ivacaftor ()
VX-561 ()
Ivacaftor d9 ()
Ivacaftor-d19 ()
P&D ID
PD009194
CAS
873054-44-5
1413431-07-8
1134822-00-6
1134822-07-3
1413431-22-7
Tags
drug candidate
natural product
drug
available
Approved by
EMA
FDA
First approval
2012
Drug Status
investigational
approved
Drug indication
Cystic fibrosis
Max Phase
Phase 4
Phase 3
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
ABSORPTION
Ivacaftor is well absorbed in the gastrointestinal tract.[A179674] 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.[L6838]
HALF-LIFE
In a clinical study, the apparent terminal half-life was approximately 12 hours following a single dose of ivacaftor.[L6838] One source mentions the half-life ranges from 12 to 14 hours.[A179674]
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.[L768,L6838]; ; When used in combination with the drug [DB09280] 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.[L6814];
ROE
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.[A179674,L6838]
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.[L6814]
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.[A179674,L6838]
DESCRIPTION
Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, the net effect of which is increased chloride channel opening.
(GtoPdb)
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 [DB09280], 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.[L6838] When combined with tezacaftor, significant improvements in lung function have been observed in clinical studies.[L6814] Ivacaftor was not found to increase the QTc interval in a clinically significant manner.[L6838]; ; 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. [L6838] This list was expanded by the FDA in May 2017 from 10 to 33 to accommodate more rare mutations.[L768]; ; 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.[L6838]
MOA
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 (ÎF508), 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.[A20301] 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.[A20305] 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.[A17564] 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.[A17564]; ; 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 [A20298, A20299]. 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 [L6838].
DESCRIPTION
Ivacaftor hydrate is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
1
Organisms
1
Compound Sets
28
AdooQ Bioactive Compound Library
Axon Medchem Screening Library
BOC Sciences Bioactive Compounds
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2017/18
Concise Guide to Pharmacology 2019/20
Concise Guide to Pharmacology 2021/22
Concise Guide to Pharmacology 2023/24
Drug Repurposing Hub
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
Mcule NIBR MoA Box Subset
MedChem Express Bioactive Compound Library
NCATS Inxight Approved Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
Other bioactive compounds
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
59
Molecular Weight
392.21
Hydrogen Bond Acceptors
3
Hydrogen Bond Donors
3
Rotatable Bonds
2
Ring Count
3
Aromatic Ring Count
3
cLogP
5.08
TPSA
82.19
Fraction CSP3
0.33
Chiral centers
0.0
Largest ring
6.0
QED
0.57
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
Autophagy
CFTR
F508del-CFTR
G551D-CFTR
CFTR potentiator
Pathway
Membrane Transporter/Ion Channel
Member status
member
MOA
CFTR Channel Activators
CFTR channel potentiator
Indication
cystic fibrosis
Solubility
Soluble in DMSO
Source data
