ivacaftor
Brand: Kalydeco
Prototype Drug
Drug Class: CFTR potentiator
Drug Family: CFTR modulator
Subclass: cystic fibrosis transmembrane conductance regulator (CFTR) modulator
Organ Systems: respiratory
Mechanism of Action
Directly potentiates mutant CFTR protein channel gating; binds to CFTR and increases the probability of channel opening, enhancing chloride and bicarbonate transport across airway epithelial cells in patients with gating mutations (G551D most common) — does not correct CFTR processing defects (folding mutations like F508del).
CFTR protein (gating mutations: G551D and others)
Indications
- cystic fibrosis in patients 4 months and older with at least one CFTR gating mutation (e.g., G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R) or other responsive mutations per FDA-approved list
Contraindications
- concomitant strong CYP3A4 inhibitors (dose reduction required) or inducers (may lose efficacy)
- hypersensitivity
Adverse Effects
Common
- headache
- upper respiratory infection
- nasal congestion
- abdominal pain
- elevated transaminases
- rash
Serious
- elevated ALT/AST (monitoring required)
- cataracts (particularly in pediatric patients)
- blood pressure elevation
Pharmacokinetics (ADME)
| Absorption | oral; bioavailability increased approximately 3-fold with high-fat meals; administer with fat-containing food |
| Distribution | Vd approximately 353 L; 99% protein bound |
| Metabolism | extensive hepatic CYP3A4; active metabolites M1 and M6 |
| Excretion | fecal (~87%) as metabolites; minimal renal (<6.6%) |
| Half-life | approximately 12 hours |
| Onset | lung function improvement within 2 weeks |
| Peak | 4 hours |
| Duration | 12 hours (twice-daily dosing) |
| Protein Binding | 99% |
| Vd | approximately 353 L |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, telithromycin) | increase ivacaftor AUC up to 8.5-fold; reduce ivacaftor dose to 150 mg twice weekly | major |
| strong CYP3A4 inducers (rifampin, rifabutin, carbamazepine, phenytoin) | reduce ivacaftor AUC up to 9-fold; avoid combination — loss of CF efficacy | major |
| CYP3A4 substrates (digoxin, cyclosporine) | ivacaftor inhibits CYP3A4 and P-gp; monitor levels of sensitive substrates | moderate |
Nursing Considerations
- Administer with fat-containing food (e.g., butter, peanut butter, eggs, cheese) to maximize absorption; foods high in fat (full-fat dairy) provide 2-3 fold increase in exposure compared with fasting.
- Monitor ALT and AST every 3 months during the first year of therapy, then annually; suspend ivacaftor if transaminases exceed 5 times the upper limit of normal.
- Screen pediatric patients for lens opacities before initiating and periodically during therapy; cataracts have been reported in pediatric patients receiving ivacaftor.
- Confirm the patient's specific CFTR mutation before initiating; ivacaftor is only effective in patients with gating mutations — patients with F508del alone (most common CF mutation) do not respond to ivacaftor monotherapy.
Clinical Pearls
- Ivacaftor was the first approved CFTR modulator (2012), establishing the principle of mutation-specific pharmacotherapy in CF; it targets gating mutations (about 5% of CF patients in the US) and dramatically improves sweat chloride, FEV1, weight, and quality of life.
- Despite remarkable efficacy in gating mutation patients, ivacaftor alone does not benefit the 85% of CF patients with F508del mutations — the CFTR protein is misfolded and degraded before reaching the cell surface; correctors (lumacaftor, tezacaftor, elexacaftor) are needed to address this problem.
Safety Profile
Pregnancy generally-safe
Lactation use-with-caution
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Guideline Update pending
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.