Indications
Ivacaftor, marketed as Kalydeco, is approved for treating·h and older with at least one responsive CFTR mutation, as determined by clinical or in vitro assays. In combination therapy, Ivacaftor is used with lumacaftor as Orkambi for CF patients aged one year and older who are homozygous for the F508del mutation. Genetic testing·his mutation if the patient's genotype is unknown. When combined with tezacaftor in Symdeko, Ivacaftor treats CF in patients aged 12 and older with at least one CFTR mutation or proven homozygous F508del mutation. Additionally, Ivacaftor, combined with tezacaftor and elexacaftor in Trikafta, serves CF patients 12 years and older harboring·harmacodynamics
Ivacaftor works by enhancing·he gating·he CFTR protein, improving·hology, unlike lumacaftor which corrects protein misfolding·have demonstrated significant benefits from Ivacaftor, including·hanced lung·hloride levels, increased weight gain, and overall symptom improvement. When combined with tezacaftor, further improvements in lung·have been noted. Importantly, Ivacaftor does not significantly affect the QTc interval. While it does not notably benefit those with the delta F508 mutation when administered alone, it significantly improves lung·her mutations. It is crucial, however, to monitor liver transaminase levels due to potential drug-induced elevation.
Absorption
Ivacaftor is efficiently absorbed from the gastrointestinal tract, particularly when taken with fat-containing·hich can enhance its absorption by 2.5 to 4 times. The drug reaches its peak plasma concentration approximately four hours post-administration when consumed with such foods, with a Cmax of 768 ng·hr/mL.
Metabolism
Extensively metabolized in humans, Ivacaftor primarily undergoes biotransformation through CYP3A enzymes. It produces two significant metabolites: M1, which is partially active and exhibits about one-sixth of Ivacaftor's efficacy, and M6, which is pharmacologically inactive and contributes less than one-fiftieth of Ivacaftor's activity.
Mechanism of Action
Ivacaftor serves as a potentiator of the CFTR protein, a crucial ion channel responsible for transporting chloride and sodium ions across the cell membranes of the lungs, pancreas, and other organs. Genetic mutations in the CFTR gene can lead to the protein being produced in insufficient quantities, misfolded, or functioning abnormally, resulting in disrupted fluid and ion transport across cell membranes. Ivacaftor enhances CF symptoms and addresses underlying disease pathology by increasing the probability of the CFTR protein channel remaining open, thereby improving gating mechanisms in patients with defective CFTR gating. The effectiveness of ivacaftor-mediated CFTR chloride transport is contingent upon the presence of sufficient CFTR protein on the cell surface and the responsiveness of the particular mutant CFTR protein to ivacaftor's potentiating effects.
