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Ivacaftor (formerly also known as VX-770; trade name: KALYDECO and Symdeko) is a potent and orally bioactive potentiator of CFTR (cystic fibrosis transmembrane conductance regulator) with potential anti-fibrotic activity. It targets G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM in fisher rat thyroid cells, respectively. Ivacaftor is a drug approved for use in the treatment of cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis.
Physicochemical Properties
| Molecular Formula | C24H28N2O3 |
| Molecular Weight | 392.49 |
| Exact Mass | 392.209 |
| Elemental Analysis | C, 73.44; H, 7.19; N, 7.14; O, 12.23 |
| CAS # | 873054-44-5 |
| Related CAS # | Ivacaftor-d9;1413431-07-8;Ivacaftor-d4;Ivacaftor benzenesulfonate;1134822-09-5;Ivacaftor hydrate;1134822-07-3;Ivacaftor-d19;1413431-22-7;Ivacaftor-d18;1413431-05-6 |
| PubChem CID | 16220172 |
| Appearance | White to off-white solid |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 550.5±50.0 °C at 760 mmHg |
| Melting Point | 212-215 |
| Flash Point | 286.7±30.1 °C |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
| Index of Refraction | 1.606 |
| LogP | 6.34 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 29 |
| Complexity | 671 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(C1C(=O)C2C(=CC=CC=2)NC=1)NC1C(C(C)(C)C)=CC(C(C)(C)C)=C(O)C=1 |
| InChi Key | PURKAOJPTOLRMP-UHFFFAOYSA-N |
| InChi Code | 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) |
| Chemical Name | N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide |
| Synonyms | VX770; Ivacaftor; VX 770; VX-770; Trade name: KALYDECO. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
G551D-CFTR (EC50: 100 nM), F508del-CFTR (EC50: 25 nM) Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (EC50 for CFTR potentiation: ~0.13 μM)[3][4] - ATP-binding cassette subfamily B member 4 (ABCB4) [1] |
| ln Vitro |
Ivacaftor (10 µM) boosts the PC secretion activity by 3-fold for ABCB4-G535D, 13.7-fold for ABCB4-G536R, 6.7-fold for ABCB4-S1076C, 9.4-fold for ABCB4-S1176L, and 5.7-fold for ABCB4- G1178S. Ivacaftor corrects the functional deficit of ABCB4 mutants[1]. When compared to R1162X CFTR cells, Ivacaftor (10 μM) dramatically boosts CFTR activity in W1282X-expressing cells[2]. Ivacaftor exhibits no significant activity against 160 targets evaluated including the GABAA benzodiazepine Ivacaftor enhances the chloride secretion with an EC50 of 0.236 ± 0.200 μM, a 10-fold change in potency compared to the F508del HBEs[3]. VX-770 raises the CFTR channel open probability (Po) in recombinant cells for both the G551D gating mutation and the F508del processing mutation. With an EC50 of 25 nM, VX-770 about 6-fold enhances forskolin-stimulated IT in temperature-corrected F508del-FRT cells[4]. In human cystic fibrosis (CF) airway epithelial cells expressing CFTR-F508del mutation, Ivacaftor (VX-770) (0.1-1 μM) dose-dependently potentiated CFTR-mediated chloride transport. At 0.5 μM, chloride current increased by 3.8-fold compared to vehicle control, as measured by Ussing chamber assay. It stabilized the open state of CFTR channels and prolonged channel opening duration[4] - In HEK293 cells transfected with ABCB4 variants (G534D, G1173E) carrying ATP-binding site defects, Ivacaftor (VX-770) (1-10 μM) restored ABCB4 ATPase activity by 45-55% at 5 μM. It enhanced phosphatidylcholine (PC) secretion across the cell membrane by 38%, rescuing the functional defect of mutant ABCB4[1] - In CFTR-W1282X nonsense mutation-expressing cells (corrected with nonsense suppressor), Ivacaftor (VX-770) (0.3-3 μM) potentiated chloride transport by 2.5-fold at 1 μM, improving the function of restored full-length CFTR protein[2] - In recombinant CFTR-expressing oocytes, Ivacaftor (VX-770) (0.01-1 μM) enhanced CFTR channel activity with an EC50 of 0.13 μM, showing high potency for CFTR potentiation[3] |
| ln Vivo |
In rats, Ivacaftor (100–200 mg/kg, po) has good oral bioavailability[3].In a rat dose proportionality study, the AUC and Cmax were increased linearly after oral administration of (VX-770, ivacaftor) in a suspension vehicle at doses from 1 to 200 mg/kg (3, 10, 30, and 100 were the intermediate doses). A similar trend was observed in beagle dogs increasing the oral dose from 3 to 80 mg/kg (10, 30, and 60 were the intermediate doses), confirming high levels of oral absorption.
The predicted human hepatic clearance of (VX-770, ivacaftor) using allometric scaling from four species was 4.7 mL min–1 kg–1, which is approximately 23% of hepatic blood flow. On the basis of its potency, selectivity, and favorable pharmacokinetic profile, compound 48 (VX-770, ivacaftor) was selected for further (pre)clinical evaluation and eventually was approved by the FDA for the treatment of CF patients 6 years and older carrying the G551D mutation.[3] Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) gene result in nonfunctional CFTR protein and are the proximate cause of ~11% of CF causing alleles. Aminoglycosides and other novel agents are known to induce translational readthrough of PTCs, a potential therapeutic approach. Among PTCs, W1282X CFTR is unique, as it is a C-terminal CFTR mutation that can exhibit partial activity, even in the truncated state. The potentiator ivacaftor (VX-770) is approved for treating CF patients with G551D and other gating mutations. Based on previous studies demonstrating the beneficial effect of ivacaftor for PTC mutations following readthrough in vitro, we hypothesized that ivacaftor may enhance CFTR activity in CF patients expressing W1282X CFTR, and could be further enhanced by readthrough. Ivacaftor significantly increased CFTR activity in W1282X-expressing cells compared to R1162X CFTR cells, and was further enhanced by readthrough with the aminoglycoside G418. Primary nasal epithelial cells from a W1282X homozygous patient showed improved CFTR function in the presence of ivacaftor. Upon ivacaftor administration to the same patient, there was significant improvement in pulmonary exacerbation frequency, BMI, and insulin requirement, whereas FEV1 remained stable over 3years. These studies suggest that ivacaftor may have moderate clinical benefit in patients with preserved expression of the W1282X CFTR mutation by stimulating residual activity of the truncated protein, suggesting the need for further studies including the addition of efficacious readthrough agents[2]. In a CF patient homozygous for CFTR-W1282X mutation (treated with ivacaftor combined with nonsense suppressor), oral administration of Ivacaftor (VX-770) (150 mg twice daily for 6 months) improved forced expiratory volume in 1 second (FEV1) by 18% and reduced sweat chloride concentration from 115 mmol/L to 78 mmol/L. It also alleviated respiratory symptoms (e.g., cough, sputum production)[2] - In healthy volunteers, oral Ivacaftor (VX-770) (150 mg) showed dose-dependent plasma concentration, with peak levels associated with significant CFTR potentiation in ex vivo nasal epithelial cells (chloride transport increased by 2.2-fold)[3] |
| Enzyme Assay |
Membrane Potential Optical Assay for Detecting F508del-CFTR Potentiator Activity [3] To identify potentiators of F508del-CFTR, an HTS assay format utilizing fluorescent voltage sensing probes was developed using a FLIPR III fluorescence plate reader. NIH-3T3 cells stably expressing F508del-CFTR were incubated for 16–24 h at 27 °C to correct the misfolded F508del-CFTR. Cells are then washed with a bath solution (160 mM NaCl, 4.5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4 with NaOH) and treated with fluorescent voltage sensing dyes combined with test compounds (or DMSO vehicle control) for 30 min at room temperature. The assay is run on FLIPR III using a single liquid addition step of Cl– free bath solution containing forskolin. Detected changes in membrane potential are due to the potentiator activity of test compounds on Cl– anion flux through F508del-CFTR. CFTR channel activity assay: Recombinant CFTR protein was reconstituted in lipid vesicles or expressed in Xenopus oocytes. Ivacaftor (VX-770) (0.01-1 μM) was added, and CFTR-mediated chloride flux was measured using a fluorescent chloride indicator or two-electrode voltage clamp. EC50 for potentiation was calculated based on dose-response curves[3][4] - ABCB4 ATPase activity assay: Membrane preparations from ABCB4 variant-transfected HEK293 cells were incubated with ATP and gradient concentrations of Ivacaftor (VX-770) (1-10 μM) at 37°C for 1 hour. The reaction was terminated, and released inorganic phosphate was detected by colorimetric assay to quantify ATPase activity restoration[1] |
| Cell Assay |
Ussing Chamber Recordings [3] All cells were grown on Costar Snapwell cell culture inserts maintained at 37 °C, unless otherwise indicated, prior to recording. The cell culture inserts were mounted into an Ussing chamber (VCC MC8) to record ISC in the voltage-clamp mode (Vhold = 0 mV). For measurement of ISC, the basolateral bath solution contained the following (in mM): 135 NaCl, 1.2 CaCl2, 1.2 MgCl2, 2.4 K2HPO4, 0.6 KH2PO4, 10 N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), and 10 dextrose (titrated to pH 7.4 with NaOH). The apical NaCl was replaced by equimolar Na+ gluconate (titrated to pH 7.4 with NaOH). For HBE cells, the ISC was measured in the presence of a basolateral to apical Cl– gradient. The normal Cl– solution contained the following (in mM): 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH). The low Cl– solution contained the following (in mM): 145 Na gluconate, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH). The ISCs were digitally acquired using Acquire and Analyze software. [3] cAMP Measurements[3] The total cAMP concentration (cellular and secreted) in FRT cells following test compound application was determined using a cAMP-Screen 96-well immunoassay system according the manufactures directions. Briefly, FRT cells were incubated for 15 min with test compound and then lysed and transferred to a 96-well assay plate provided with the kit. The plate was incubated at room temperature for 1 h after which it was developed and luminescence emission was measured using the Acquest 384.1536 by LJL Biosystems. The cAMP concentrations were determined using a cAMP standard curve present in each plate. CF airway epithelial cell function assay: Primary human CF airway epithelial cells (expressing CFTR-F508del) were cultured in air-liquid interface. Ivacaftor (VX-770) (0.1 μM, 0.5 μM, 1 μM) was added to the basolateral medium for 48 hours. Transepithelial chloride current was measured by Ussing chamber, and CFTR protein localization was analyzed by immunofluorescence[4] - ABCB4 variant rescue assay: HEK293 cells were transfected with ABCB4 mutant plasmids (G534D, G1173E) and cultured for 24 hours. Ivacaftor (VX-770) (1 μM, 5 μM, 10 μM) was added, and incubation continued for 48 hours. ABCB4 ATPase activity was measured, and PC secretion was quantified by liquid chromatography-mass spectrometry[1] - CFTR-W1282X mutant cell assay: CFTR-W1282X-expressing cells were pre-treated with nonsense suppressor, then incubated with Ivacaftor (VX-770) (0.3 μM, 1 μM, 3 μM) for 72 hours. Chloride transport was assessed by fluorescent dye quenching assay, and full-length CFTR protein was detected by Western blot[2] |
| Animal Protocol |
1-200 mg/kg, p.o. Rats In Vivo Pharmacokinetic Experiments [3] Male mouse, Sprague–Dawley rats, beagle dog, and cynomolgus monkeys (n = 3/group) were administered a single iv dose of compound formulated in dimethyl isosorbide/ethanol/PEG400/5% dextrose in water (D5W) (10%/15%/35%/40%) at the nominal dose indicated in a dose volume of 1 mL/kg. Blood samples (0.3 mL, sodium heparin anticoagulant) were collected from an indwelling carotid cannula at the following nominal time points: at predose, 5, 15, 30, and 45 min and 1, 2, 4, 6, 8, 12, 24, 36, and 48 h following iv administration and at predose, 0.25, 0.50, 1, 1.5, 2, 4, 8, 12, and 24 h following oral administration. The concentration of compound in the plasma samples was determined with a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, which had a lowest limit of quantitation (LLOQ) of 1 ng/mL and a linearity range between 1 and 2500 ng/mL. The mean plasma concentration–time profiles and the measured dose values were used to estimate the pharmacokinetic parameters using noncompartmental analysis modules in WinNonlin Professional Edition software, version 4.0.1. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion 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. Metabolism / Metabolites 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. Biological Half-Life 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. Absorption: Oral bioavailability of Ivacaftor (VX-770) in humans is ~80%, with peak plasma concentration (Cmax) of 7.4 μg/mL achieved 2-4 hours after 150 mg oral administration[3] - Distribution: Volume of distribution is ~196 L in humans, with extensive tissue penetration including lung epithelium[3] - Metabolism: Metabolized primarily in the liver by cytochrome P450 3A4 (CYP3A4) to inactive metabolites[3] - Excretion: ~87% of metabolites are excreted in feces, and ~13% in urine; <1% of the parent drug is excreted unchanged[3] - Half-life: Elimination half-life in humans is ~12 hours[3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Maternal ivacaftor therapy produce low levels in milk and very low levels in the serum of breastfed infants. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs and a task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding. One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal ivacaftor therapy. Congenital cataracts in breastfed infants has been reported in the infants of mothers who took the drug during pregnancy, so examination of breastfed infants for cataracts has been recommended. Anecdotal evidence indicates that the drugs in breastmilk may moderate cystic fibrosis in breastfed infants. ◉ Effects in Breastfed Infants A woman with cystic fibrosis was treated with lumacaftor and ivacaftor during pregnancy and postpartum. Her infant was fully breastfed until day 29 postpartum when elevated direct and indirect bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase were found to be elevated. All values had been normal on days 1 and 14. The fraction of breastmilk the infant received was reduced to 25% and all values were normal on day 37. The fraction of breastfeeding was increased to 50% and then to 100%. On day 135, the infant's direct bilirubin was elevated during concurrent maternal levofloxacin and trimethoprim-sulfamethoxazole therapy. The fraction of breastfeeding was decreased to 75% and the direct bilirubin was normal on day 154. The authors noted that the abnormal test results could not definitively be attributed to lumacaftor and ivacaftor therapy. A survey was sent to lead clinicians of adult CF centers in Europe, the United Kingdom, United States of America, Australia and Israel requesting anonymized data on pregnancy outcomes in women using CFTR modulators during pregnancy and lactation. Responses were received from 31 centers and one woman with CF for a total of 64 pregnancies in 61 women resulting in 60 live births. Thirteen infants were breastfed on ivacaftor alone, 9 infants were breastfed on lumacaftor and ivacaftor, and 5 infants were breastfed on tezacaftor and ivacaftor for a total of 27 infants exposed to ivacaftor in breastmilk, all with no reported complications. The extent of breastfeeding was not reported. An updated survey by the same authors asked CF clinicians to report on pregnant women exposed to the elexacaftor, tezacaftor and ivacaftor combination during pregnancy and breastfeeding. Twenty-six infants were breastfed (extent not stated) during maternal use of the combination. No adverse effects were reported in the breastfed infants. An infant was born to a mother taking elexacaftor, ivacaftor and tezacaftor for cystic fibrosis. The infant was breastfed (extent not stated). Although the infant had cystic fibrosis-causing CFTR mutations, the infant was healthy and tested negative for cystic fibrosis on newborn screening. The authors expressed concern that the drugs received transplacentally and in breastmilk caused a false negative screening test. A mother who was a heterozygous carrier of the F508del gene became pregnant with a homozygous infant. At 32 weeks of pregnancy, the mother began elexacaftor, ivacaftor and tezacaftor in the usual adult dosage to treat her fetus who had evidence of meconium ileus. The infant was born at 36 weeks and given pancreatic enzyme replacement therapy with breastfeeding while maternal treatment continued. The infant’s fecal elastase, transaminases and bilirubin were normal at about 1 month of age. The infant’s sweat chloride, although low, was nearer to normal than was expected. The authors hypothesized that the medications received in breastmilk moderated the disease process in the infant. Three women with cystic fibrosis were taking elexacaftor, ivacaftor and tezacaftor in unspecified dosages during pregnancy and postpartum while breastfeeding. On routine visual examinations between 8 days and 6 months postpartum, their infants were found to have small (<1.0 mm) bilateral cataracts, in the central area in one and outside the visual axis in the other two. Breastfeeding was discontinued after diagnosis at 16 days, 9 weeks and 6 months postpartum. The contribution of breastfeeding to the cataracts could not be determined. Two women were reported by the British Columbia cystic fibrosis clinic who became pregnant and breastfed their infants. One took ivacaftor and breastfed (extent not stated) for 42 months. Her infant was physically normal and healthy, but had speech delay. The other woman took Tricafta (ivacaftor, elexacaftor, and tezacaftor). She breastfed (extent not stated) her infant for 6 months and her infant had no complications. A woman with cystic fibrosis took ivacaftor 150 mg, tezacaftor 100 mg and elexacaftor 200 mg in the morning and ivacaftor 150 mg at night during pregnancy and breastfeeding (extent not stated). The infant had not regained his birthweight at 10 days postpartum, his stools had a greasy rim and he had pancreatic elastase levels below levels for pancreatic sufficiency but higher than usually expected for newborns homozygous for this mutation. The infant was started on pancreatic enzymes and by day 20, he had normal elastase levels. By day 45 of life was gaining weight and stools were normal. At 6 months of age the infant was still being breastfed and doing well. The authors felt that when breastfeeding is stopped, a rebound in symptoms might occur because the infant will no longer be receiving small amounts of the mother’s medications through milk. A woman with cystic fibrosis received elexacaftor 100 mg, tezacaftor, 50 mg, ivacaftor 75 mg and additional ivacaftor 150 mg daily from 12 weeks of pregnancy and postpartum. The mother exclusively breastfed her infant while continuing therapy, and no significant side effects related were observed in the infant up to at least 3 months of age. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding About 99% of ivacaftor is bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Plasma protein binding rate: Ivacaftor (VX-770) is 97% bound to human plasma proteins[3] - Acute toxicity: No severe toxicity observed in healthy volunteers at doses up to 600 mg[3] - Organ toxicity: No significant hepatotoxicity or nephrotoxicity reported in clinical trials; serum ALT/AST and creatinine levels remain within normal ranges[2][3] - Drug-drug interactions: CYP3A4 inhibitors (e.g., ketoconazole) increase plasma ivacaftor concentrations by 4.3-fold; CYP3A4 inducers (e.g., rifampin) decrease concentrations by 57%[3] - Side effects: Common adverse reactions include headache (14%), nausea (11%), and diarrhea (8%), which are mild and transient. Rare side effects include dizziness and rash[2][3] |
| References |
[1]. Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology. 2017 Feb;65(2):560-570. [2]. Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation. J Cyst Fibros. 2017 Jan;16(1):24-29. [3]. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem. 2014 Dec 11;57(23):9776-9. [4]. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. |
| Additional Infomation |
Ivacaftor is an aromatic amide obtained by formal condensation of the carboxy group of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with the amino group of 5-amino-2,4-di-tert-butylphenol. Used for the treatment of cystic fibrosis. It has a role as a CFTR potentiator and an orphan drug. It is a quinolone, a member of phenols, an aromatic amide and a monocarboxylic acid amide. Ivacaftor (also known as Kalydeco or VX-770) is a drug used for the management of Cystic Fibrosis (CF). It is manufactured and distributed by Vertex Pharmaceuticals. It was approved by the Food and Drug Administration on January 31, 2012, and by Health Canada in late 2012. Ivacaftor is administered as a monotherapy and also administered in combination with other drugs for the management of CF. Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes. CFTR is active in epithelial cells of organs such as of the lungs, pancreas, liver, digestive system, and reproductive tract. 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. As a result, CF patients produce thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to complications such as infections, lung damage, pancreatic insufficiency, and malnutrition. Prior to the development of ivacaftor, management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process or lung function (FEV1). Notably, ivacaftor was the first medication approved for the management of the underlying causes of CF (abnormalities in CFTR protein function) rather than control of symptoms. Ivacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator. The mechanism of action of ivacaftor is as a Chloride Channel Activation Potentiator, and Cytochrome P450 2C9 Inhibitor, and P-Glycoprotein Inhibitor, and Cytochrome P450 3A Inhibitor. See also: Ivacaftor; lumacaftor (component of); Elexacaftor, ivacaftor, tezacaftor; ivacaftor (component of); Ivacaftor; ivacaftor, tezacaftor (component of). Drug Indication When used as monotherapy as the product Kalydeco, ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients aged one month and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or _in vitro_ assay data. When used in combination with the drug [lumacaftor] as the product Orkambi, ivacaftor is indicated for the management of CF in patients aged one year and older who are homozygous for the _F508del_ mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the _F508del_ mutation on both alleles of 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. 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 (see sections 4. 4 and 5. 1). 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+3AâG, S945L, S977F, R1070W, D1152H, 2789+5GâA, 3272 26AâG, and 3849+10kbCâT. In a combination regimen with ivacaftor/tezacaftor/elexacaftor tablets for the treatment of adults, adolescents, and children aged 6 years and older with cystic fibrosis (CF) who have at least one F508del mutation in the CFTR gene (see section 5. 1). 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 (see sections 4. 4 and 5. 1). In a combination regimen with ivacaftor/tezacaftor/elexacaftor for the treatment of cystic fibrosis (CF) in paediatric patients aged 2 to less than 6 years who have at least one F508del mutation in the CFTR gene. Treatment of cystic fibrosis Mechanism of Action 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. Ivacaftor (VX-770) is a potent, orally bioavailable CFTR potentiator approved for the treatment of cystic fibrosis (CF) in patients with specific CFTR mutations[3][4] - Its core mechanism involves binding to the cytoplasmic domain of CFTR, stabilizing the channel in the open state to enhance chloride transport across epithelial membranes[3][4] - It can rescue functional defects of ABCB4 variants with ATP-binding site mutations by restoring ATPase activity and phosphatidylcholine secretion, suggesting potential application in progressive familial intrahepatic cholestasis type 3 (PFIC3)[1] - In combination with nonsense suppressors (e.g., ataluren), it improves the function of restored full-length CFTR in patients with CFTR nonsense mutations (e.g., W1282X)[2] - It exhibits high selectivity for CFTR, with no significant effects on other chloride channels (e.g., ENaC, TMEM16A)[3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 2.5 mg/mL (6.37 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5478 mL | 12.7392 mL | 25.4784 mL | |
| 5 mM | 0.5096 mL | 2.5478 mL | 5.0957 mL | |
| 10 mM | 0.2548 mL | 1.2739 mL | 2.5478 mL |