Lumacaftor
Lumacaftor
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Lumacaftor

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Catalog Number PR936727058
CAS 936727-05-8
Description Lumacaftor is an aromatic amide obtained by formal condensation of the carboxy group of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid with the aromatic amino group of 3-(6-amino-3-methylpyridin-2-yl)benzoic acid. Used for the treatment of cystic fibrosis.
Synonyms VX-809; VX 809; VX809
IUPAC Name 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid
Molecular Weight 452.4
Molecular Formula C24H18F2N2O5
InChI UFSKUSARDNFIRC-UHFFFAOYSA-N
InChI Key InChI=1S/C24H18F2N2O5/c1-13-5-8-19(27-20(13)14-3-2-4-15(11-14)21(29)30)28-22(31)23(9-10-23)16-6-7-17-18(12-16)33-24(25,26)32-17/h2-8,11-12H,9-10H2,1H3,(H,29,30)(H,27,28,31)
Drug Categories Amines; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2B6 Inducers (strength unknown); Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C19 Inducers (strength unknown); Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C8 Inducers (strength unknown); Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP2C8 Inhibitors (strength unknown); Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP2C9 Inducers (strength unknown); Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors (strength unknown); Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inducers (strong); Cytochrome P-450 CYP3A4 Inducers; Cytochrome P-450 CYP3A4 Inducers (strong); Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Dioxoles; Heterocyclic Compounds, Fused-Ring; P-glycoprotein inducers; P-glycoprotein inhibitors; Pyridines
Drug Interactions 1,2-Benzodiazepine-The metabolism of 1,2-Benzodiazepine can be increased when combined with Lumacaftor.
Abemaciclib-The serum concentration of Abemaciclib can be decreased when it is combined with Lumacaftor.
Abiraterone-The metabolism of Abiraterone can be increased when combined with Lumacaftor.
Abrocitinib-The serum concentration of Abrocitinib can be decreased when it is combined with Lumacaftor.
Acalabrutinib-The serum concentration of Acalabrutinib can be decreased when it is combined with Lumacaftor.
Half-Life The half-life of lumacaftor is approximately 26 hours in patients with cystic fibrosis.
Isomeric SMILES CC1=C(N=C(C=C1)NC(=O)C2(CC2)C3=CC4=C(C=C3)OC(O4)(F)F)C5=CC(=CC=C5)C(=O)O
Type Small Molecule
Therapeutic Category Treatment of Cystic Fibrosis
Pharmacology

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.

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