Indications
Lumacaftor, in combination with ivacaftor as the product Orkambi, is indicated for the treatment of cystic fibrosis (CF) in patients aged one year and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Prior to initiating treatment, if a patient's genotype is undetermined, it is essential to use an FDA-cleared CF mutation test to confirm the presence of the F508del mutation on both CFTR gene alleles.
Pharmacodynamics
Research into the pharmacodynamics of lumacaftor, alone and in combination with ivacaftor, involved various clinical trials. A Phase 2 study observed patients with CF who were either homozygous or heterozygous for the F508del mutation. After receiving lumacaftor 400 mg every 12 hours for 28 days, patients subsequently added ivacaftor 250 mg every 12 hours for another 28 days. A significant reduction in sweat chloride levels was observed with these treatments, demonstrating enhanced efficacy when compared to the placebo, which did not correlate with improved lung function. Additionally, a thorough QT study indicated no significant impact on QTc intervals, a vital indicator of heart rhythm stability.
Absorption
The absorption profile of lumacaftor improves significantly when the drug is ingested with fat-containing meals, resulting in approximately double the exposure compared to a fasting state. Upon administration of multiple oral doses over the prescribed range, the lumacaftor exposure increased proportionally. The median time to reach maximum concentration (tmax) for lumacaftor is about 4.0 hours in a fed state.
Metabolism
Lumacaftor undergoes minimal metabolism and is largely excreted unchanged through the feces. When metabolic activity occurs, it primarily involves pathways of oxidation and glucuronidation. This limited metabolism contributes to its consistent pharmacokinetic profile and supports its usage in targeted CF therapy.
Mechanism of Action
Lumacaftor functions by enhancing the conformational stability of the F508del-CFTR protein, which is compromised due to the F508del mutation prevalent in cystic fibrosis. This mutation leads to protein misfolding and subsequent degradation, significantly reducing the presence of CFTR channels on the epithelial cell surface. Lumacaftor facilitates improved processing and trafficking of the mature CFTR protein, thereby increasing its presence on the cell membrane. Experimental studies in primary human bronchial epithelial cultures and other cell lines carrying the F508del-CFTR mutation have shown that lumacaftor directly interacts with the CFTR protein. This interaction enhances the quantity, stability, and function of the F508del-CFTR at the cell surface, thereby improving chloride ion transport. It is important to note that the outcomes observed in vitro may not directly translate to in vivo pharmacodynamic responses or clinical benefits.