CFTR potentiators

Overview
CFTR potentiators are a targeted class of drugs used in the treatment of cystic fibrosis (CF) caused by specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These drugs enhance the activity of the defective CFTR protein at the cell surface, improving chloride and bicarbonate transport across epithelial membranes. This helps restore hydration of airway surface liquid and improve mucociliary clearance, reducing the respiratory and gastrointestinal complications of CF.

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Mechanism of Action

• The CFTR protein functions as a cAMP-regulated chloride channel in epithelial cells of the airways, pancreas, gastrointestinal tract, and sweat glands.

• In certain mutations (notably gating mutations like G551D), the CFTR protein reaches the cell surface but has reduced channel opening probability (“gating defect”).

• CFTR potentiators bind to the defective CFTR channels and increase their open probability, allowing improved chloride ion flow.

• This effect complements CFTR correctors, which help misfolded CFTR reach the cell surface (used in combination for some mutation types).

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Available Agents

1. Ivacaftor (Kalydeco) – first-in-class CFTR potentiator.

   • Indications: CF in patients ≥1 month old with at least one CFTR mutation responsive to ivacaftor (primarily gating mutations such as G551D, G1244E, S1251N, etc.).

2. Combination Therapies including a Potentiator:

   • Lumacaftor/ivacaftor (Orkambi) – for patients homozygous for F508del mutation.

   • Tezacaftor/ivacaftor (Symdeko/Symkevi) – for F508del homozygotes and some other mutations.

   • Elexacaftor/tezacaftor/ivacaftor (Trikafta/Kaftrio) – for patients with at least one F508del mutation (broadest eligibility).
     (In these combinations, ivacaftor acts as the potentiator; the other agents are CFTR correctors.)

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Therapeutic Uses

• Cystic fibrosis in patients with specific CFTR mutations shown to be responsive to potentiation therapy.

• Mutation-specific therapy—patients must undergo CFTR genotyping before initiation.

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Dosage and Administration (Ivacaftor monotherapy)

• Adults and children ≥6 years: 150 mg orally every 12 hours with fat-containing food.

• Younger age groups: Weight-based dosing; available as granules for infants and young children.

• Combination products have fixed-dose regimens based on age and weight.

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Contraindications

• Known hypersensitivity to ivacaftor or any excipients.

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Precautions

• Hepatic impairment: Dose adjustments in moderate/severe impairment; monitor liver function.

• Drug interactions: Avoid strong CYP3A inducers (reduce efficacy); adjust dose with strong/moderate CYP3A inhibitors.

• Regular ophthalmologic exams in pediatric patients (risk of non-congenital lens opacities).

• Monitor liver function tests before and during treatment.

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Adverse Effects

• Common: Headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, diarrhea, rash, dizziness.

• Laboratory: Elevated liver transaminases.

• Less common: Cataracts (pediatric patients), hypotension (rare).

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Drug Interactions

• CYP3A4 metabolism:

  • Strong inhibitors (ketoconazole, itraconazole, clarithromycin) → increase ivacaftor levels; dose reduction required.

  • Strong inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort) → markedly decrease levels; avoid use.

• Avoid grapefruit and Seville oranges (CYP3A inhibition).