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]

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].

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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]

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]

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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].

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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]

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.

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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]

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]

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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.

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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]

Absorption, Distribution and Excretion
Ivacarto is well absorbed in the gastrointestinal tract. After co-administration with fatty foods, peak plasma concentrations were reached at 4 hours (Tmax), with a maximum concentration (Cmax) of 768 ng/mL and an AUC of 10600 ng·hr/mL. Co-administration with fatty foods is recommended as fat can increase its absorption by approximately 2.5 to 4 times. Following oral administration, ivacarto is primarily metabolized and excreted in the feces, accounting for 87.8% of the total dose. Metabolites M1 and M6 account for the majority of the total excreted dose, at 22% and 43%, respectively. Very little ivacarto is excreted unchanged in the urine. In healthy volunteers, after oral administration of 150 mg every 12 hours for 7 consecutive days in a postprandial state, the mean (± standard deviation) apparent volume of distribution was 353 (122) L.
The clearance/plasma concentration (CL/F) (standard deviation) after a 150 mg dose in healthy subjects was 17.3 (8.4) L/hr.
Metabolism/Metabolites
Ivacarto is extensively metabolized in the human body. In vitro and clinical studies have shown that ivacarto is primarily metabolized via CYP3A. The major metabolites are M1 and M6. Although M1 has only about one-sixth the potency of the parent compound ivacarto, it is still considered pharmacologically active. On the other hand, M6 is not considered pharmacologically active because it represents less than one-fiftieth of the activity of the parent compound.
Biological Half-Life
In one clinical study, the apparent terminal half-life of ivacarto was approximately 12 hours after a single dose. Data indicate that its half-life is 12 to 14 hours.

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Absorption: Ivacatol (VX-770) has an oral bioavailability of approximately 80% in humans. After oral administration of 150 mg, the peak plasma concentration (Cmax) is 7.4 μg/mL, which is reached 2-4 hours later[3].
-Distribution: The volume of distribution in the human body is approximately 196 L, and it can penetrate extensively into tissues including the lung epithelium[3].
-Metabolism: It is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) into inactive metabolites[3].
-Excretion: Approximately 87% of the metabolites are excreted in feces, and approximately 13% are excreted in urine; less than 1% of the original drug is excreted unchanged[3].
-Half-life: The elimination half-life in the human body is approximately 12 hours[3].

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
After mothers take ivacatocin, the drug concentration in breast milk is low, and the drug concentration in the serum of breastfed infants is extremely low. An international survey of cystic fibrosis centers found no adverse reactions in infants breastfed by mothers taking these medications. A working group of respiratory experts from Europe, Australia, and New Zealand also believes that these medications are likely safe during lactation. One breastfed infant experienced transient increases in bilirubin and liver enzymes during the mother's treatment, but it could not be determined whether this was related to the medication in the breast milk. Until more data are available, it is recommended to monitor bilirubin and liver enzymes in breastfed infants during the mother's ivacatocin treatment. There are reports of congenital cataracts in infants breastfed by mothers who took the medication during pregnancy; therefore, cataract screening is recommended for breastfed infants. Anecdotal evidence suggests that the medication in breast milk may have a mitigating effect on cystic fibrosis in breastfed infants.
◉ Impact on Breastfed Infants
A woman with cystic fibrosis received lumacaftor and ivacaftor during pregnancy and postpartum. Her infant was exclusively breastfed until day 29 postpartum, after which elevated levels of direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase were observed in the infant. All indicators were normal on days 1 and 14 postpartum. The infant's breastfeeding rate decreased to 25%, and all indicators returned to normal by day 37. The breastfeeding rate then increased to 50%, and then to 100%. On day 135, while the mother was simultaneously receiving levofloxacin and sulfamethoxazole/trimethoprim, the infant's direct bilirubin level increased. The breastfeeding rate decreased to 75%, and direct bilirubin levels returned to normal by day 154. The authors note that the abnormal test results could not be definitively attributed to lumacaftor and ivacaftor treatment. We sent a questionnaire to chief clinicians at adult cystic fibrosis (CF) centers in Europe, the UK, the US, Australia, and Israel, requesting anonymized data on pregnancy outcomes in women using CFTR modulators during pregnancy and lactation. We received responses from 31 centers and one CF patient, involving 64 pregnancies in 61 women, resulting in 60 live births. Of these, 13 infants were breastfed with ivacaftor alone, 9 were breastfed with lumacaftor and ivacaftor, and 5 were breastfed with tezacaftor and ivacaftor, for a total of 27 infants exposed to ivacaftor through breast milk. No complications were reported in any of the infants. However, the extent of breastfeeding was not reported. A subsequent survey by the same co-authors asked CF clinicians to report cases of pregnant women exposed to combinations of elexacaftor, tezacaftor, and ivacaftor during pregnancy and lactation. Twenty-six infants were breastfed while their mothers were taking the combination therapy (feeding extent not specified). No adverse reactions were reported in the breastfed infants. One infant's mother was taking elexacaftor, ivacaftor, and tezacaftor for cystic fibrosis. This infant was breastfed (feeding extent not specified). Although the infant carried the CFTR gene mutation that causes cystic fibrosis, the infant was healthy and had a negative newborn screening result. The authors express concern that these drugs may cross the placenta and breast milk into the infant, leading to false negative screening results. A mother who was a heterozygous carrier of the F508del gene became pregnant and gave birth to a homozygous infant. At 32 weeks of gestation, the mother started taking adult-standard doses of elexacaftor, ivacaftor, and tezacaftor to treat fetal meconium intestinal obstruction. The infant was born at 36 weeks and received pancreatic enzyme replacement therapy and was breastfed after birth while the mother continued treatment. By approximately one month of age, the infants' fecal elastase, transaminase, and bilirubin levels had returned to normal. While the infants' sweat chloride levels were low, they were closer to normal than expected. The authors speculate that the medication in the breast milk may have alleviated the infants' condition. Three women with cystic fibrosis took elexadecanotoxin, ivacaftor, and tezacator during pregnancy and postpartum breastfeeding, but the specific dosages were not specified. Routine vision checks at 8 days to 6 months postpartum revealed that these infants had bilateral small cataracts (<1.0 mm), with one infant having a central cataract and the other two having cataracts off-axis. Breastfeeding was discontinued after diagnosis at 16 days, 9 weeks, and 6 months postpartum. The effect of breastfeeding on cataracts could not be determined. A BC cystic fibrosis clinic reported two cases of pregnant and breastfeeding women. One of them took ivacaftor and breastfed for 42 months (duration not specified). Her baby was physically healthy but had delayed language development. Another woman was taking Tricafta (ivacafta, elecafta, and tezacator). She breastfed her baby for 6 months (feeding duration not specified), and the baby experienced no complications. A woman with cystic fibrosis took ivacafta 150 mg, tezacator 100 mg, and elecafta 200 mg in the morning and ivacafta 150 mg in the evening during pregnancy and lactation (feeding duration not specified). Ten days after birth, the baby's weight had not returned to birth weight, stools were oily, and pancreatic elastase levels were below the standard for normal pancreatic function but above the expected level for a homozygous newborn with this mutation. The baby started taking pancreatic enzyme preparations, and by day 20, pancreatic elastase levels returned to normal. By day 45 after birth, the baby had gained weight and had normal bowel movements. At 6 months of age, the baby was still breastfed and in good health. The authors suggest that symptoms may rebound after breastfeeding is discontinued because the infant will no longer receive small amounts of the medication from the mother through breast milk. A woman with cystic fibrosis took 100 mg elecato, 50 mg tizacator, and 75 mg ivacator daily from week 12 of pregnancy, with an additional 150 mg ivacator postpartum. The mother continued exclusive breastfeeding while receiving treatment, and no significant treatment-related side effects were observed in the infant at least 3 months of age. ◉ Effects on lactation and breast milk: As of the revision date, no relevant published information was found. Protein binding: Ivacator is approximately 99% bound to plasma proteins, primarily α1-acid glycoprotein and albumin.

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Plasma protein binding rate: Ivacarto (VX-770) has a 97% binding rate to human plasma proteins[3]
-Acute toxicity: No serious toxicity was observed in healthy volunteers at doses up to 600 mg[3]
-Organ toxicity: No significant hepatotoxicity or nephrotoxicity was reported in clinical trials; serum ALT/AST and creatinine levels remained within the normal range[2][3]
-Drug interactions: CYP3A4 inhibitors (e.g., ketoconazole) increased plasma isacarto concentrations by 4.3 times; CYP3A4 inducers (e.g., rifampin) decreased concentrations by 57%[3]
-Side effects: Common adverse reactions include headache (14%), nausea (11%), and diarrhea (8%), which are usually mild and transient. Rare side effects include dizziness and rash[2][3]

[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.

Ivacaftor is an aromatic amide formed by the condensation of the carboxyl group of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with the amino group of 5-amino-2,4-di-tert-butylphenol. It is used to treat cystic fibrosis. It is a CFTR enhancer and an orphan drug. It belongs to the quinolone, phenol, aromatic amide, and monocarboxylic acid amide classes. Ivacaftor (also known as Kalydeco or VX-770) is a drug used to treat cystic fibrosis (CF). It is manufactured and marketed by Vertex Pharmaceuticals. The drug was approved by the U.S. Food and Drug Administration (FDA) on January 31, 2012, and by Health Canada at the end of 2012. Ivacaftor can be used as monotherapy or in combination with other drugs to treat cystic fibrosis. Cystic fibrosis is an autosomal recessive genetic disorder caused by one of several different mutations in the cystic fibrosis transmembrane transport regulator (CFTR) gene. CFTR protein is an ion channel involved in the transmembrane transport of chloride and sodium ions. CFTR is actively expressed in the epithelial cells of organs such as the lungs, pancreas, liver, digestive system, and reproductive tract. Alterations in the CFTR gene can lead to abnormal protein production, misfolding, or dysfunction, resulting in abnormal fluid and ion transport across the cell membrane. Therefore, patients with cystic fibrosis produce thick mucus that can clog the ducts of the organs that produce mucus, making them more susceptible to complications such as infection, lung injury, pancreatic insufficiency, and malnutrition. Before the advent of ivacaftor, treatment for cystic fibrosis (CF) focused primarily on controlling infection, providing nutritional support, clearing mucus, and relieving symptoms, rather than improving the disease itself or lung function (FEV1). Notably, ivacaftor was the first drug approved for treating the underlying cause of CF (abnormal CFTR protein function) rather than relieving symptoms. Ivacaftor is an enhancer of the cystic fibrosis transmembrane conduction regulator (CFTR). Its mechanisms of action include acting as a chloride channel activator, a cytochrome P450 2C9 inhibitor, a P-glycoprotein inhibitor, and a cytochrome P450 3A inhibitor. See also: ivacaftor; lumacaftor (component); Elexacaftor, ivacaftor, tezacaftor; ivacaftor (component); ivacaftor; ivacaftor (ivacaftor), tezacaftor (component).

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Drug Indications
When used as monotherapy (Kalydeco), ivacaftor is indicated for the treatment of cystic fibrosis (CF) patients aged 1 month or older with a single mutation in the CFTR gene and who have demonstrated sensitivity to the synergistic effect of ivacaftor based on clinical and/or in vitro data. When used in combination with the drug [lumacaftor] (Orkambi), ivacaftor is indicated for the treatment of CF patients aged 1 year or older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-approved CF mutation assay should be used to detect the presence of the F508del mutation in both alleles of the CFTR gene. When used in combination with [tezacaftor] in the product Symdeko, it is indicated for the treatment of patients aged 12 years and older with at least one mutation in the CFTR gene, or patients aged 12 years and older with CF who are confirmed 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 patients aged 12 years and older with cystic fibrosis carrying at least one _F508del_ mutation in the CFTR gene.
The indication for Kalydeco tablets is as monotherapy for the treatment of cystic fibrosis (CF) in adults, adolescents, and children aged 6 years and older and weighing 25 kg or more who carry the R117H CFTR mutation or one of the following gated (class III) mutations in the cystic fibrosis transmembrane conduction regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (see Sections 4.4 and 5.1). In combination with tezacaftor/ivacaftor tablets, this treatment is indicated 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 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, 327226A→G, and 3849+10kbC→T. Calideco granules may be used in combination with ivacator/tezacotto/elecator tablets for the treatment of cystic fibrosis (CF) in adults, adolescents, and children aged 6 years and older who carry at least one CFTR gene F508del mutation (see Section 5.1). Calideco granules are indicated for the treatment of infants at least 4 months of age, toddlers and children weighing 5 kg to less than 25 kg who have cystic fibrosis (CF) and carry the R117H CFTR mutation or one of the following CFTR gene-gated (class III) mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (see Sections 4.4 and 5.1). For the treatment of cystic fibrosis (CF) in children aged 2 to 6 years with at least one F508del mutation in the CFTR gene, it must be used in combination with ivacaftor/tezacaftor/elexacaftor.
Treatment of Cystic Fibrosis

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Mechanism of Action
Multiple CFTR mutations are associated with the cystic fibrosis phenotype, and the severity of the disease varies. The most common mutation is F508del-CFTR or delta-F508 (ΔF508), affecting approximately 70% of CF patients worldwide. This mutation results in the deletion of phenylalanine at position 508, impairing CFTR protein production and significantly reducing the number of ion transporters on the cell membrane. Ivacaftor monotherapy has failed to benefit patients carrying the delta-F508 mutation, likely due to insufficient availability of protein on the cell membrane to interact with the drug and enhance its effect. The second most common mutation is G551D, affecting 4-5% of cystic fibrosis (CF) patients worldwide. This mutation is a missense mutation, indicating an adequate quantity of cell surface protein, but altered channel opening and closing mechanisms. Ivacasoto is suitable for treating CF patients carrying this mutation because it binds to the CFTR protein on the cell membrane and enhances its channel opening ability. Ivacasoto works by enhancing the activity of the CFTR protein, an ion channel involved in the transport of chloride and sodium ions across the cell membranes of the lungs, pancreas, and other organs. Alterations in the CFTR gene can lead to abnormal protein production, misfolding, or function, resulting in abnormal fluid and ion transport across the cell membrane. Ivacasoto improves CF symptoms and underlying disease pathology by enhancing the probability (or gating) of CFTR protein channel opening, and is suitable for patients with impaired CFTR gating mechanisms. The overall level of ivaccato-mediated CFTR chloride transport depends on the quantity of CFTR protein on the cell surface and the degree to which the specific mutated CFTR protein responds to the enhancing effect of ivaccato.

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Ivacarto (VX-770) is a potent, orally bioavailable CFTR enhancer approved for the treatment of patients with cystic fibrosis (CF) carrying specific CFTR mutations[3][4].
- Its core mechanism is to bind to the cytoplasmic domain of CFTR, stabilizing the channel to remain open, thereby enhancing chloride ion transport across the epithelial cell membrane[3][4].
- It can rescue the functional defects of ABCB4 variants with ATP-binding site mutations by restoring ATPase activity and phosphatidylcholine secretion, suggesting its potential use in the treatment of progressive familial intrahepatic cholestasis type 3 (PFIC3)[1].
- When used in combination with nonsense inhibitors (e.g., atalulren), it improves the function of restored full-length CFTR in patients carrying CFTR nonsense mutations (e.g., W1282X) [2]
- It is highly selective for CFTR and has no significant effect on other chloride channels (e.g., ENaC, TMEM16A) [3]

C24H28N2O3

392.49

392.209

C, 73.44; H, 7.19; N, 7.14; O, 12.23

873054-44-5

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

16220172

White to off-white solid

1.2±0.1 g/cm3

550.5±50.0 °C at 760 mmHg

212-215

286.7±30.1 °C

0.0±1.5 mmHg at 25°C

1.606

6.34

3

4

4

29

671

0

O=C(C1C(=O)C2C(=CC=CC=2)NC=1)NC1C(C(C)(C)C)=CC(C(C)(C)C)=C(O)C=1

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)

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

VX770; Ivacaftor; VX 770; VX-770; Trade name: KALYDECO.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)