Ivacaftor

Ivacaftor (brand name Kalydeco) is a CFTR potentiator approved for the treatment of certain cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. It represents the first targeted therapy designed to enhance the function of the defective CFTR protein at the cell surface.

This medication is indicated for people with cystic fibrosis who carry specific gating mutations in CFTR. By increasing the probability that the CFTR chloride channel remains open, ivacaftor improves chloride and fluid transport across epithelial cells in the lungs and other organs.

The mechanism of action involves potentiation of CFTR channels, leading to improved lung function, weight gain, fewer pulmonary exacerbations, and reductions in sweat chloride concentration.

The key gene influencing ivacaftor response is CFTR, which encodes a chloride channel critical for fluid balance in the lungs, pancreas, intestines, and other tissues. Proper CFTR function helps maintain clear airways and normal digestive processes.

Mutations in CFTR can impair channel gating (opening), trafficking (delivery to the cell surface), or synthesis. Ivacaftor specifically targets gating mutations, helping defective CFTR channels stay open longer to restore chloride transport and alleviate disease symptoms.

Genetic variants in CFTR determine who will benefit from ivacaftor. Patients with gating mutations (ivacaftor responsive) see marked clinical improvements, while those with non-responsive or irrelevant mutations experience little to no benefit. If genotype information is unavailable, standard dosing with clinical monitoring is recommended.

Ivacaftor Responsive

• Effect: Enhanced CFTR channel opening and chloride transport
• Clinical consequence: Improved lung function, weight gain, and fewer pulmonary exacerbations
• Side effects: Common mild to moderate events such as headache, abdominal pain, and upper respiratory infections

Ivacaftor Non-Responsive

• Effect: No meaningful change in CFTR activity
• Clinical consequence: No significant improvement in respiratory or nutritional outcomes
• Side effects: May still experience typical ivacaftor side effects (e.g., headache) without clinical benefit

Ivacaftor Irrelevant

• Effect: Genotype does not affect ivacaftor response
• Clinical consequence: Standard clinical outcomes expected
• Side effects: Typical ivacaftor safety profile applies (e.g., diarrhea, headache)

Indeterminate/Not Available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

CFTR Dosing Guideline

Examples of alternative CFTR modulators include lumacaftor/ivacaftor (Orkambi), tezacaftor/ivacaftor (Symdeko), and elexacaftor/tezacaftor/ivacaftor (Trikafta). These combination therapies may be considered for patients who do not respond to ivacaftor monotherapy.

• CPIC – Guideline for Ivacaftor and CFTR