lumacaftor

Lumacaftor is a small-molecule drug used in the treatment of cystic fibrosis (CF) as part of a combination therapy. It acts as a CFTR (cystic fibrosis transmembrane conductance regulator) corrector and is co-formulated with ivacaftor, a CFTR potentiator, in fixed-dose regimens marketed in some regions as lumacaftor/ivacaftor (Orkambi).

Mechanism of action: In many CF patients, especially those with the common F508del mutation, CFTR proteins misfold and are degraded before reaching the cell surface. Lumacaftor improves the folding and trafficking of the mutant CFTR protein, increasing its presence at the cell surface. Ivacaftor then enhances the activity of the channels that are present, improving chloride transport across the epithelial surface. The combination aims to restore some CFTR function that is reduced by the mutation.

Medical use: The lumacaftor/ivacaftor combination is indicated for cystic fibrosis patients who are homozygous for the F508del mutation. It is taken orally, usually twice daily, as a fixed-dose combination. Regulatory approvals and age indications have varied by region and over time.

Safety and pharmacology: Common adverse effects include respiratory symptoms such as chest tightness or shortness of breath, as well as nausea, diarrhea, and elevated liver enzymes. There is a risk of liver injury, and routine monitoring of liver function tests is recommended. Lumacaftor is a substrate and inducer of cytochrome P450 enzymes, which can affect the levels of other medications; careful consideration of drug interactions is advised.

Development and status: Lumacaftor was developed by Vertex Pharmaceuticals and is one component of CFTR-modulating therapy, with use dependent on genetic genotype and regional approvals.