FDA Approved drug,Jan 2012Ivacaftor

Generic name: IvacaftorTrade name: KalydecoCode designation: VX-770IUPAC Name : N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

Date of approval : January 31, 2012

Innovative company:Ivacaftor has been developed by Vertex Pharmaceuticals (which it is also marketed by), and the Cystic Fibrosis Foundation.

ATC code R07AX02CAS number: 873054-44-5

PubChemCID : 16220172ChemSpider: 17347474UNII: 1Y740ILL1Z

SMILES : O=C\2c1c(cccc1)N/C=C/2C(=O)Nc3cc(O)c(cc3C(C)(C)C)C(C)(C)C

InChI:1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)

Dosage form: oral tablets 150mg

Indication:For the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.

Mechanism of Action • Ivacaftor is a potentiator of the CFTR protein. • The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. • Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the G551D-CFTR protein.

Cystic FibrosisCystic fibrosis is an autosomal genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine.

It is characterized by abnormal transport of chloride and sodium across epithelium, leading to thick, viscous secretions.

CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This gene is required to regulate the components of sweat, digestive juices, and mucus.

Location : in epithelial cells of lungs, pancreas, liver, sweat glands, digestive tract and reproductive system.

CFTR :

• Transmembrane glycoprotein • ABC family (ATP Binding Cassette)• 1480 amino acids• 170 kDa• 5 domains

2 transmembrane domains (TM1, TM2), 6 alpha helixes, chloride channel

2 nucleotid binding domains (NBD1, NBD2), cytoplasmic, ATP fixation and hydrolysis

1 regulatory domain (RD) : phosphorylation by PKA, AMPc dependant.

Rescue of deltaF508-CFTR trafficking and gating in human cystic fibrosis airway cultures by small moleculesChloride channels as drug targets Alan S. Verkman* and Luis J. V. Galietta‡

http://upload.wikimedia.org/wikipedia/commons/0/09/CFTR.jpg

Molecular structure of the CFTR protein

http://www.massgenomics.org/wp-content/uploads/2011/02/cftrdiagramlarge.gif

• 1480 amino acids

http://upload.wikimedia.org/wikipedia/commons/0/03/Protein_CFTR_PDB_1xmi.png

NBD1 of human CFTR complexed with ATP.

Activation of CFTR

• Activation of CFTR PKA-regulated AMPc dependant phosphorylation of the RD NBD1 : ATP hydrolysis open NBD2 : ATP hydrolysis close

• Passage of chloride ions and bicarbonate through the plasma membrane.

Biochimie médicale Marqueurs actuels et perspectives 2e édition Jean-Louis Beaudeux Geneviève Durand Medecine Sciences Publications Lavoisier

http://www.cfgenetherapy.org.uk/images/CFTR3D.jpg

Role of the CFTR channel

Nature : transmembrane glycoprotein from ATP- binding cassette family.

Function :• Epithelial anion channel involved in

chloride transport.• Maintenance of exocrine• Inhibition of the sodium reabsorption

by the channel ENac• Non-water reabsorption

Interface inserm/SFP – Nouvelles thérapies dans la muciviscidose en 2011. I.Sermet-Gaudelus, M. Le Bourgeois, J. de Blc, G.Lenoir, A. EdelmanVertex Pharmaceuticals

Consequence of loss of function Interferences with CFTR folding, trafficking, membrane stability,

and channel gating. Absent or defective CFTR causes abnormal ion transport.

Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulator Am J Physiol Lung Cell Mol Physiol 301:L587-L597, 2011. First published 1 July 2011

http://www.nature.com/polopoly_fs/7.2729.1328623738!/image/CF.jpg_gen/derivatives/lightbox/CF.jpg

Most frequent defects associated with CF

Different classes of mutation:Classe I: Defective protein production

Classe II: Defective protein processingΔF508

Classe III: Defective protein regulationG511D

Classe IV: Defective channel conductance

Classe V: Reduce synthesis

Pharmacological therapy for cystic fibrosis: From bench to bedside Frédéric Becqa,*, Marcus A. Mallb, David N. Sheppardc, Massimo Conesed,e, Olga Zegarra-Moranf

Location of the amino acid alterations associatedwith CFTR gatingmutations tested in this study.

Most frequent defects

• ΔF508-CFTR Reduced CFTR density and activity

in the apical membrane Impaired epithelial cell function Deletion of Phe (codon 508) 90% of CF patients 50% homozygous for the ΔF508-

CFTR ΔF508-CFTR, which occurs in >90%

of patients in the U.S., creates a protein that does not fold normally and is degraded by the cell.

Rescue of deltaF508-CFTR trafficking and gating in human cystic fibrosis airway cultures by small molecules and Gene Mutations in Cystic Fibrosis, Vertex.

Most frequent defects

• G551D-CFTRDysfunctional CFTRMutation codon 551

(Gly Asp) Impaired epithelial cell

function

• France: 6.000 patientsF508del / G551D : 53; 0,9%

Registre Francais de la Mucoviscdose : rapport de données 2009 and Gene Mutations in Cystic Fibrosis, VertexThe Cystic Fibrosis Mutation G551D Alters the Non-Michaelis Menten Behavior of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel and Abolishes the Inhibitory Genistein Binding Site

Pharmacokinetics:

Absorption The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

Distribution Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.

Pharmacokinetics:

Metabolism Ivacaftor is extensively metabolized in humans ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Elimination Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion.

Dose:Adults and pediatric patients age 6 years and older: one 150 mg tablet taken orally every 12 hours with fat-containing food. • Reduce dose in patients with moderate and severe hepatic impairment. • Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.

ADVERSE REACTIONS:The most common adverse drug reactions to KALYDECO were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness.