Tezacaftor/ivacaftor and ivacaftor

Tezacaftor/ivacaftor and ivacaftor Uses, Dosage, Side Effects, Food Interaction and all others data.

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.

Tezacaftor is a drug of the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator class. It was developed by Vertex Pharmaceuticals and FDA approved in combination with ivacaftor to manage cystic fibrosis. This drug was approved by the FDA on February 12, 2018.

Clinical studies have shown a significant decrease in sweat chloride and an increase in the forced expiratory volume (FEV), a measure of lung function, following Tevacaftor/Ivacaftor therapy. Phase 3 clinical studies have shown that a significant increase in forced expiratory volume was attained at 4 and 8 weeks after initiating this drug. The above effects lead to improvement of the respiratory symptoms of cystic fibrosis. Tezacaftor does not induce clinically significant QT prolongation. When given with ivacaftor, tezacaftor can lead to liver transaminase elevations. Testing of transaminases (ALT and AST) levels should occur before starting this combination every 3 months during the first year of treatment, and every year afterwards. Patients with a history of transaminase elevations should be monitored more frequently.

Tezacaftor/ivacaftor and ivacaftor
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Tezacaftor/ivacaftor and ivacaftor
Generic	ivacaftor + tezacaftor
Type	Oral
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator used alone or in combination products to treat cystic fibrosis in patients who have specific genetic mutations that are responsive to the medication.

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.

Tezacaftor is a medication used to treat homozygous or heterozygous F508del mutation cystic fibrosis.

Tezacaftor is combined with ivacaftor in one product for the treatment of cystic fibrosis (CF) in patients aged 12 years or older with two copies of the F508del gene mutation or at least one mutation in the CFTR gene that is responsive to this drug.

Tezacaftor, when used in combination with ivacaftor and elexacaftor in the product Trikafta, is also indicated for the treatment of CF in patients 12 years of age and older that have at least one F508del mutation in the CFTR gene.

Tezacaftor/ivacaftor and ivacaftor is also used to associated treatment for these conditions: Cystic Fibrosis (CF)Cystic Fibrosis (CF)

How Tezacaftor/ivacaftor and ivacaftor works

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 .

The transport of charged ions across cell membranes is normally achieved through the actions of the cystic fibrosis transmembrane regulator (CFTR) protein. This protein acts as a channel and allows for the passage of chloride and sodium. This process affects the movement of water in and out of the tissues and impacts the production of mucus that lubricates and protects certain organs and body tissues, including the lungs. In the F508del mutation of the CFTR gene, one amino acid is deleted at the position 508, therefore, the CFTR channel function is compromised, resulting in thickened mucus secretions. CFTR correctors such as tezacaftor aim to repair F508del cellular misprocessing. This is done by modulating the position of the CFTR protein on the cell surface to the correct position, allowing for adequate ion channel formation and increased in water and salt movement through the cell membrane. The concomitant use of ivacaftor is intended to maintain an open channel, increasing the transport of chloride, reducing thick mucus production.

Toxicity

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.

The LD50 of an oral dose in rats is >2000 mg/kg.

Overdose symptoms may include dizziness and diarrhea. There have been no reports to this date of tezacaftor overdose, but the highest dose of 450 mg every 12 hours commonly resulted in reports of dizziness and diarrhea. No antidote exists for treating an overdose with this drug. General supportive measures should be undertaken along with monitoring of vital signs and close monitoring of clinical status.

Volume of Distribution

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 apparent volume of distribution of tezacaftor was 271 L in a study of patients in the fed state who received 100 mg of tezacaftor every 12 hours.

Elimination Route

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.

The Cmax, Tmax and AUC of tezacaftor, when administered with ivacaftor, are 5.95 mcg/ml, 2-6 h, and 84.5 mcg.h/ml respectively. Exposure of tezacaftor/ivacaftor increases 3-fold when it is administered with a high-fat meal.

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.

The apparent half-life of tezacaftor is approximately 57.2 hours.

Clearance

The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

The apparent clearance of tezacaftor has been measured at 1.31 L/h for patients in the fed state during a clinical trial.

Elimination Route

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, the majority of tezacaftor dose (72%) is found excreted in the feces either unchanged or as its metabolite, M2. About 14% of the administered dose is found excreted in the urine as the metabolite, M2. It was noted that less than 1% of the administered dose is excreted unchanged in the urine and thus, renal excretion is not the major elimination pathway.