Ivacaftor

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.

Ivacaftor is also used to associated treatment for these conditions: Cystic Fibrosis (CF)

How 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 .

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.

Food Interaction

• Take with a high fat meal. Co-administration with a high fat meal increases exposure to ivacaftor.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state.

Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges.

All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products.

A typical cystic fibrosis diet will satisfy this requirement.

Ivacaftor Drug Interaction

Moderate: loratadine, loratadine / pseudoephedrine, sulfamethoxazole / trimethoprimUnknown: charcoal, fluticasone / salmeterol, fluticasone / salmeterol, umeclidinium / vilanterol, alpha 1-proteinase inhibitor, diphenhydramine, fluticasone / vilanterol, aztreonam, ciprofloxacin, ubiquinone, pancrelipase, sodium iodide, ivacaftor / lumacaftor, acetaminophen, elexacaftor / ivacaftor / tezacaftor, acetaminophen, cetirizine

Ivacaftor Disease Interaction

Moderate: cataracts, hepatic impairment, renal impairment

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.

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.

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.

Clearance

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

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.

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