Condition

Cystic fibrosis (CF) is known to cause your lungs to produce extra-thick, sticky mucus. This mucus builds up and clogs the airways and becomes a source of inflammation and infection that can lead to lung damage. As the white blood cells fight the infection caught in the mucus, they leave behind remains called extracellular DNA. The buildup of these remains makes the mucus in lungs affected by CF even thicker than before, leaving the lungs even more vulnerable to irreversible structural changes, progressive decline in function, and eventually respiratory failure. Disease severity for CF is based on lung capacity measured by spirometry pulmonary function tests such as forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC). Normal pulmonary disease is defined as FEV1 percentage of greater than 90% predicted, 70-89% predicted for mildly impaired, 40-69% predicted for moderately impaired, and an FEV1 percentage of less than 40% predicted is defined as severely impaired. Despite several supportive therapies; the median age of death is still 27 years. CF affects about 30,000 people in the United States and about 70,000 people globally.

CF is a serious genetic condition. It caused by reduced quantity and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein due to mutations in the CFTR gene in CF patients. The CFTR protein is an epithelial chloride channel that aids in regulating salt and water absorption and secretion and pH balance in multiple organs, including the lungs, pancreas and other gastrointestinal organs, and sweat glands. Decreased CFTR chloride transport results in multisystem pathology, beginning at birth.  Salt loss may contribute to symptoms early in life and is the traditional diagnostic test for CF. Despite several supportive therapies; the median age of death is still 27 years.

Treatments

For Infections:

  • Antibiotics (ciprofloxacin and tobramycin)

To open airways in the lungs or keep them open:

  • Bronchodilators (albuterol or salmeterol), which are used to make breathing easier. They may also make it easier to cough up mucus.
  • Anticholinergics (Atrovent)

To control the amount and thickness of mucus:

  • Pulmozyme is a purified solution for inhalation of recombinant human deoxyribonuclease (rhDNase) which reduces lung sputum viscosity and improves secretion clearance. Pulmozyme is recommended for the chronic treatment of moderate to severe CF pulmonary disease. The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid Nebulizer System. Most patients gain optimal benefit from regular daily use of Pulmozyme. In studies in which Pulmozyme was given in an intermittent regimen, improvement in pulmonary function was lost on cessation of therapy. Patients should therefore be advised to take their medication every day without a break.
  • Saltwater solution (hypertonic saline). This is sometimes used to help clear mucus from the lungs. It is low-cost, and it may help reduce inflammation in the airways.

To reduce inflammation:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen)
  • Membrane stabilizers (such as cromolyn)
  • Corticosteroids (such as fluticasone or prednisone)

With digestive enzymes:

  • Enzyme replacement therapy (such as Creon or Pancreaze)

With cystic fibrosis transmembrane conductance regulator (CFTR) potentiators:

  • Ivacaftor (CFTR), a potentiator, is used for treatment of CF in patients age 2 years and older who have the G551D mutation in the CFTR gene.

2-5 years, <14 kg: 50 mg granules PO q12hr before or after eating fat-containing food

2-5 years, ≥14 kg: 75 mg granules PO q12hr before or after eating fat-containing food

6-17 years: 150 mg PO q12hr before or after eating fat-containing food

 Dose needs to be reduced to 150 mg PO twice-a-week when co-administrating with strong or moderate CYP3A inhibitors. Co-administration with a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s Wort is not recommended.

 This compound offers a novel approach to the treatment of CF, as it is the only marketed drug that targets the underlying cause of this lethal condition, instead of the downstream disease processes that occur as a result of lacking or defective CFTR. Available clinical trial data indicate that compared with placebo, ivacaftor has superior efficacy for improving respiratory function, and it has been shown to lower the risk of pulmonary exacerbations. The adverse-effect profile of ivacaftor does not differ substantially from placebo, but patients will need to be monitored for hepatic function and potential drug interactions during treatment.

 Newly approved therapy

If the patient is homozygous for the F508del mutation in the CFTR gene, needs a CFTR corrector with Ivacaftor (Lumacaftor/Ivacaftor (Orkambi), approved by FDA in July 2015. Lumacaftor corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR proteins. The combination is indicated for cystic fibrosis in patients aged 12 yr or older who are homozygous for the F508del mutation in the CFTR gene: ≥12 yr: 1 tablet (Lumacaftor/Ivacaftor: 200 mg/125 mg) PO q12hr with fat containing food. Study data show that lumacaftor in combination with ivacaftor provides benefit for patients with cystic fibrosis homozygous for the F508del CFTR mutation The most common side effects of Orkambi include shortness of breath, upper respiratory tract infection, nausea, diarrhea, and rash. Women who took Orkambi also had increased menstrual abnormalities such as increased bleeding.

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