Ivacaftor

392.49100

392.49

1Y740ILL1Z

DTXSID00236281

R07AX30|R07AX02|R07AX31|R07AX|R - Respiratory system

29333990

85.68000

5.6

Solid

1.187 g/cm3

212-215

550.4ºC at 760 mmHg

286.7ºC

1.606

H2O: <0.05 µg/mL

11.08, 1.5

11.08, 1.5

|Warning|H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]|P201, P202, P261, P264, P271, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 3 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

In large randomized controlled trials of ivacaftor with or without lumacaftor or tezacaftor, up to 25% of subjects had some degree of serum aminotransferase elevations during therapy. The elevations, however, were generally transient and mild and were above 3 times the upper limit of normal (ULN) in only 2% to 5% of patients. The abnormalities were usually asymptomatic and often resolved spontaneously without dose adjustment. Furthermore, in several studies, similar rates of serum enzyme elevations were noted in the placebo treated groups. Nevertheless, serum aminotransferase elevations resulted in dose modification or interruption in 1% to 2% of patients on ivacaftor alone or with lumacaftor or tezacaftor.

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

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. 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. 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.|FDA Label|Orkambi tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation in the CFTR gene.Orkambi granules are indicated for the treatment of cystic fibrosis (CF) in children aged 2 years and older who are homozygous for the F508del mutation in the CFTR gene.|Kalydeco tablets are indicated:As monotherapy for the treatment of adults, adolescents, and children aged 6 years and older and weighing 25 kg or more with cystic fibrosis (CF) who have an R117H CFTR mutation or one of the following gating (class III) mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.In a combination regimen with tezacaftor/ivacaftor tablets for the treatment of adults, adolescents, and children aged 6 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the CFTR gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.In a combination regimen with ivacaftor /tezacaftor /elexacaftor tablets for the treatment of adults and adolescents aged 12 years and older with cystic fibrosis (CF) who have at least one F508del mutation in the CFTR gene.Kalydeco granules are indicated for the treatment of infants aged at least 4 months, toddlers and children weighing 5 kg to less than 25 kg with cystic fibrosis (CF) who have an R117H CFTR mutation or one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.|Symkevi is indicated in a combination regimen with ivacaftor tablets for the treatment of patients with cystic fibrosis (CF) aged 6 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.|Treatment of cystic fibrosis|Kaftrio is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Ivacaftor, lumacaftor, tezacaftor and elexacaftor are orally available potentiators or correctors of the cystic fibrosis transmembrane conductance regulator (CFTR) that are used to treat patients with cystic fibrosis with specific mutations of the CFTR. Ivacaftor alone or in combination with lumacaftor or tezacaftor has been associated with low rate of transient serum enzyme elevations during treatment, but not with clinically apparent acute liver injury with jaundice, while the addition of elexacaftor to ivacaftor and tezacaftor has been implicated in a higher rate of serum enzyme elevations (up to 10% of patients) and to rare instances of clinically apparent liver injury with jaundice.

Cystic Fibrosis Agents

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. When combined with tezacaftor, significant improvements in lung function have been observed in clinical studies. Ivacaftor was not found to increase the QTc interval in a clinically significant manner. 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. This list was expanded by the FDA in May 2017 from 10 to 33 to accommodate more rare mutations. 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.

A class of drugs that stimulate chloride ion influx through cell membrane channels. (See all compounds classified as Chloride Channel Agonists.)

Ivacaftor is well absorbed in the gastrointestinal tract. 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.|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.|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.|The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

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.

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

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. 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. 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. 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. 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. 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.

3-quinolinecarboxamide, N-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-1,4-dihydro-4-oxo-

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