Indications
Tezacaftor, in combination with ivacaftor, is indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years or older. This treatment is specifically for individuals who have two copies of the F508del gene mutation or at least one mutation in the CFTR gene that is responsive to this medication. Additionally, when combined with ivacaftor and elexacaftor as part of the Trikafta product, tezacaftor is also approved for the treatment of CF in patients aged 12 and older possessing at least one F508del mutation in the CFTR gene.
Pharmacodynamics
Clinical investigations highlight a substantial reduction in sweat chloride levels and an improvement in forced expiratory volume (FEV), an indicator of lung function, following therapy with tezacaftor/ivacaftor. Notably, Phase 3 clinical studies show a marked increase in forced expiratory volume at both 4 and 8 weeks after commencing treatment, leading to better respiratory outcomes in cystic fibrosis patients. Tezacaftor does not cause clinically significant QT interval prolongation, yet, when administered with ivacaftor, it may result in elevated liver transaminase levels. Therefore, it is recommended to monitor transaminase levels (ALT and AST) before starting the combination treatment, every three months in the first year, and annually thereafter. Patients with a history of elevated transaminase levels should be monitored more frequently.
Absorption
When administered with ivacaftor, tezacaftor exhibits a Cmax of 5.95 mcg/ml, Tmax ranging from 2 to 6 hours, and an AUC of 84.5 mcg.h/ml. The exposure of tezacaftor/ivacaftor significantly increases threefold when taken with a high-fat meal, thereby influencing its absorption profile.
Metabolism
Tezacaftor is extensively metabolized by the enzymes CYP3A4 and CYP3A5 in humans, resulting in three primary circulating metabolites: M1, M2, and M5. The M1 metabolite is active and possesses similar efficacy to tezacaftor itself, while the M2 metabolite has markedly reduced activity, and M5 is considered inactive. Additionally, there is a circulating metabolite M3, which is the glucuronide form of tezacaftor.
Mechanism of Action
Tezacaftor functions by addressing cellular misprocessing associated with the F508del mutation of the cystic fibrosis transmembrane regulator (CFTR) gene. Normally, CFTR proteins facilitate the transport of chloride and sodium ions across cell membranes, a process critical for regulating water movement in tissues and thereby influencing mucus production. In cystic fibrosis patients with the F508del mutation, the deletion of an amino acid at position 508 impairs CFTR function, resulting in the secretion of thick, viscous mucus. Tezacaftor acts as a CFTR corrector by enhancing the proper positioning of the CFTR protein on the cell surface, thus enabling the formation of functional ion channels and promoting the movement of water and salt across the cell membrane. When used in combination with ivacaftor, which helps maintain an open CFTR channel, the efficacy of ion transport is increased, effectively reducing mucus viscosity and improving respiratory function.
