Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

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. While 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 the effect 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. Other data indicate a half-life ranging from 12 to 14 hours.

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 believe that after breastfeeding is discontinued, symptoms may rebound because the infant can no longer ingest small amounts of the medication from the mother through breast milk. A woman with cystic fibrosis took 100 mg elezacador, 50 mg tezazacador, and 75 mg ivacacador daily from week 12 of pregnancy, and continued taking 150 mg ivacacador postpartum. The mother maintained exclusive breastfeeding throughout the treatment period, and no significant drug-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: Approximately 99% of ivacacador is bound to plasma proteins, primarily α1-acid glycoprotein and albumin.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

[2]. 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.

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. Ivacasor 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. Ivacasor 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 lung, 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. Ivacasor improves cystic fibrosis (CF) symptoms and underlying pathological mechanisms by enhancing the probability (or gating ability) of CFTR protein channels, particularly in patients with impaired CFTR gating mechanisms. The overall level of CFTR chloride ion transport mediated by ivacasor 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 ivacasor.

C24H10D18N2O3

410.60

410.323

1413431-05-6

Ivacaftor;873054-44-5;Ivacaftor-d4

16220172

White to off-white solid powder

212-215

5.154

3

4

4

29

671

0

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-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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