Lumacaftor is a pharmaceutical drug that acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It is a small molecule CFTR corrector (VX-809) that stabilizes misfolded F508del CFTR in the endoplasmic reticulum, promoting maturation to the Golgi and increasing the proportion of mature band C CFTR detectable by biochemical assays. In cellular models lumacaftor increases chloride channel expression at the plasma membrane and is used clinically in combination with a potentiator to augment channel activity. Pharmacologically it has low aqueous solubility, is orally administered as a solid dosage form, is a moderate to strong inducer of CYP3A enzymes and several transporters and undergoes hepatic metabolism, which requires attention to drug interactions in coadministration settings.
Parent: Lumacaftor
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Parent: Lumacaftor
Parent: Lumacaftor
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Parent: Lumacaftor
Typical active pharmaceutical ingredient specifications for lumacaftor include an assay by validated HPLC method of not less than 98.0% of the declared amount. Typical limits for related substances are total impurities equal to or below 1.0% w/w and individual known related compounds commonly limited as follows: Related compound A (common degradant or synthetic impurity) not more than 0.5% w/w, Related compound B not more than 0.2% w/w, Related compound C (oxidation product) not more than 0.1% w/w; any unspecified single impurity usually controlled at or below 0.05% w/w. These example limits align with ICH Q3A/B principles for reporting and identification thresholds and are used by manufacturers as a starting point for validated specifications and stability limits.
Lumacaftor is used to correct the folding and trafficking defect of F508del CFTR in cystic fibrosis and is administered in combination with a CFTR potentiator to improve clinical outcomes in patients who are homozygous for the F508del mutation.
Lumacaftor acts as a pharmacological chaperone that stabilizes misfolded F508del CFTR in the endoplasmic reticulum, facilitating processing and trafficking to the cell surface where more channels are available for activation by potentiators.
Ivacaftor is a CFTR potentiator that increases the open probability of CFTR channels already present at the cell surface, whereas lumacaftor is a CFTR corrector that promotes proper folding and trafficking of mutant CFTR to increase the amount of channel protein at the membrane; they are complementary and are often given together in combination therapy.
Lumacaftor is also known by its research code VX-809 and is an active ingredient in combination products marketed under proprietary names when combined with ivacaftor.
