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.
|Brand mixtures||Not Available|
|Mass Spec||Not Available|
|Class||Quinolines and Derivatives|
|Direct parent||Quinoline Carboxamides|
|Alternative parents||Hydroquinolones; Anilides; Hydroquinolines; Cumenes; Nicotinamides; Aminophenols; Secondary Carboxylic Acid Amides; Enolates; Carboxylic Acids; Polyamines; Enols|
|Substituents||dihydroquinolone; acetanilide; dihydroquinoline; cumene; nicotinamide; pyridine carboxylic acid or derivative; aminophenol; phenol derivative; pyridine; benzene; secondary carboxylic acid amide; carboxamide group; polyamine; enol; enolate; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound|
|Classification description||This compound belongs to the quinoline carboxamides. These are quinolines in which the quinoline ring system is substituted by one or more carboxamide groups.|
|Indication||For the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.|
|Pharmacodynamics||Ivacaftor 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 action||Cystic 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.|
|Absorption||The 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 binding||Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.|
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 elimination||Following 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 life||12 hours following a single dose|
The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
|Toxicity||There 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.|
|SNP Mediated Effects|
|SNP Mediated Adverse Drug Reactions||Not Available|
|Predicted ADMET features|
|Synthesis Reference||Not Available|
|PDB Entries||Not Available|
|FDA label||show(239 KB)|
Pharmacological action: yes
|Cystic fibrosis transmembrane conductance regulator||P13569||Details|
- 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
Pharmacological action: unknown
- FDA label