Cystic fibrosis agents
Information about Cystic fibrosis agents
Ivacaftor, lumacaftor and tezacaftor are orally available potentiators or correctors of the cystic fibrosis transmembrane conductance regulator (CFTR) that are used to treat patients with cystic fibrosis with specific mutations of the CFTR.
Liver safety of Cystic fibrosis agents
Ivacaftor alone or in combination with lumacaftor or tezacaftor has been associated with transient serum enzyme elevations during treatment, but neither agent has been convincingly implicated in cases of clinically apparent acute liver injury with jaundice.
Mechanism of action of Cystic fibrosis agents
Cystic fibrosis (CF) is a severe inherited disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, which results in impaired clearance of mucous secretions leading to progressive pancreatic and pulmonary dysfunction, considerable disability and early mortality. CF is considered the most common, fatal genetic disorder among Caucasians, affecting approximately 1:2000 persons of European descent. Disease manifestations generally arise in childhood and include pancreatic insufficiency, poor nutrition, failure to thrive and progressive lung disease with frequent respiratory infections and pulmonary exacerbations. Survival is poor, but has improved greatly with medical interventions and attention to maintenance of rigorous pulmonary hygiene, preventive or rapid treatment of respiratory infections and proper nutritional management. The discovery that the disease was caused by mutations in the CFTR gene led to a focused search for small molecules that might improve, correct or potentiate abnormal CFTR function. A major problem was the diversity of mutations found in CF and the variability in how these mutations affected gene function (proper folding of the mature CFTR protein, trafficking of the protein to the proper place in the plasma membrane, channel opening and maintenance of the open configuration). Nevertheless, several agents were identified that were potentiators or correctors ("tor") of the CFTR ("caf") and could improve respiratory function, sense of well being and nutrition and decrease pulmonary exacerbations in patients with CF who had agent-specific mutations in the CFTR gene. Currently, three such agents are available clinically – ivacaftor, lumacaftor and tezacaftor. Several other CFTR potentiators are in various stages of development.
Ivacaftor (eye" va kaf' tor) was the first CFTR modulator to become available for use in the United States. It potentiates the opening of the CFTR channel in patients who harbor at least one mutation in the CFTR gene that is responsive to invacaftor based upon clinical or in vitro assay data, such as the Gly551Asp (also abbreviated as G551D) CFTR mutation. Ivacaftor was approved in the United States for use in patients with the CFTR Gly551Asp mutation in 2012 and is available as monotherapy in tablets of 150 mg and as oral granules in packets of 50 and 75 mg under the brand name Kalydeco. The recommended dose in adults and children above 6 years of age is 150 mg orally every 12 hours. The dose in children less than 6 years of age is based upon body weight. The Gly551Asp mutation is found in approximately 5% of patients with CF.
Lumacaftor (loo" ma kaf' tor) is a "corrector" of the CFTR and was the second agent to gain approval as therapy of CF, but only in combination with ivacaftor, and specifically for patients who are homozygous for the Phe508del (F508del) mutation in the CFTR. Phen508del is the most frequent mutation in CFTR found in patients with CF and is associated with a lack of trafficking of the transporter to the cell surface. In vitro, lumacaftor was found to partially correct this trafficking error. Lumacaftor combined with ivacaftor was approved for use in patients homozygous for Phe508del CFTR in 2015 and is available as tablets consisting of 200 mg of lumacaftor and 125 mg of ivacaftor under the brand name Orkambi. Side effects of these agents are generally mild, but can include headache,nasal congestion, abdominal pain, diarrhea, nausea, dizziness and rash.
Tezacaftor (tez" a kaf' tor) is a "corrector" of the CFTR and was the third agent to gain approval, but only in combination with ivacaftor, and specifically for patients who are homozygous for the Phe508Del (F508del) mutation in the CFTR or are heterozygous and have another mutation in CFTR found in patients with CF and is associated with a lack of trafficking of the transporter to the cell surface. In vitro, tezacaftor was found to partially correct this trafficking error. Tezacaftor combined with ivacaftor was approved for use in the United States as therapy for patients with cystic fibrosis in 2018 and is available as tablets of fixed dose of 100 mg tezacaftor with 150 mg of ivacaftor co-packaged with tablets of 150 mg of ivacaftor alone under the brand name Symdeko. Side effects of these agents are generally mild but can include headache,nasal congestion, abdominal pain, diarrhea, nausea, dizziness and rash.
genetic disorder agents
- gaucher disease agents
glucosylceramide synthase inhibitors (substrate restriction therapy)
lysosomal acid lipase deficiency agents
- agalsidase beta, alglucosidase alfa, alpha1-proteinase inhibitor, elosulfase alfa, galsulfase, idursulfase, laronidase, pegademase
Huntington disease agents
Urea Cycle Disorder Agents