Ivacaftor

Các tên gọi khác (3) :

Ivacaftorum
Kalydeco
VX-770

Thuốc Gốc

Small Molecule

CAS: 873054-44-5

ATC: R07AX02

CTHH: C₂₄H₂₈N₂O₃

PTK: 392.4907

Ivacaftor (also known as Kalydeco or VX-770) is a drug for the treatment of cystic fibrosis, developed by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation. FDA approved on January 31, 2012.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₄H₂₈N₂O₃

Phân tử khối

392.4907

Monoisotopic mass

392.209992772

InChI

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)

InChI Key

InChIKey=PURKAOJPTOLRMP-UHFFFAOYSA-N

IUPAC Name

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

Traditional IUPAC Name

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide

SMILES

CC(C)(C)C1=CC(=C(O)C=C1NC(=O)C1=CNC2=CC=CC=C2C1=O)C(C)(C)C

Độ hòa tan

Insoluble (<0.05 µg/mL)

logP

5.76

logS

-5.3

pKa (strongest acidic)

6.57

pKa (Strongest Basic)

-0.95

PSA

78.43 Å²

Refractivity

118.68 m³·mol^-1

Polarizability

43.04 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-1

Number of Rings

Bioavailability

Dược Lực Học : Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR). In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

Cơ Chế Tác Dụng : Ivacaftor (also known as Kalydeco or VX-770) is a drug for the treatment of cystic fibrosis, developed by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation. FDA approved on January 31, 2012. Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator, which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. The defect, which is caused by a mutation in the individual's DNA, can be in any of several locations along the protein, each of which interferes with a different function of the protein. One mutation, G551D, lets the CFTR protein reach the epithelial cell surface, but doesn't let it transport chloride through the ion channel. 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.

Dược Động Học :

▧ Absorption :
The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF. When given a single oral dose of 150 mg to healthy subjects, the parameters were as follows: Tmax = 4 hours; Cmax = 768 ng/mL; AUC = 10600 ng*hr/mL; Time to steady state, 12 hour dosing = 3-5 days Following repeated doses for ivacaftor, accumulation occurs. When given with a fatty meal, exposure increases 2-4 fold.
▧ Volume of Distribution :
The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of Ivacaftor in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
▧ Protein binding :
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.
▧ Metabolism :
Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that 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.
▧ Route of Elimination :
Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent.
▧ Half Life :
12 hours following a single dose
▧ Clearance :
The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

Độc Tính : There have been no reports of overdose with Ivacaftor. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events.

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

Tương Tác Thuốc :

Alvimopan Decreases levels by P-glycoprotein (MDR-1) efflux transporter. Can significantly increase systemic exposure to P-glycoprotein substrates.
Bendamustine Increases levels of bendamustine by P-glycoprotein (MDR-1) efflux transporter.
Carbamazepine Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
Clarithromycin Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Erythromycin Moderate CYP3A4 inhibitors may increase levels of ivacaftor. Consider dose reduction.
Etravirine Ivacaftor, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid this combination.
Fluconazole Moderate CYP3A4 inhibitors may increase levels of ivacaftor. Consider dose reduction.
Itraconazole Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Ketoconazole Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Pazopanib Inhibits p-glycoprotein and affects heptatic metabolism via CYP3A4 therefore increases levels of pazopanib. Consider alternate therapy.
Phenobarbital Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
Phenytoin Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
Posaconazole Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Rifabutin Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
Rifampicin Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
St. John's Wort Strong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
Telithromycin Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.
Tofacitinib Ivacaftor, when used in combination with tofacitinib, may increase tofaciitinib concentrations, It is recommended to monitor therapy for signs of toxicity or worsened side effects.
Vismodegib P-glycoprotein inhibitors may increase the chance of adverse drug reactions. Consider using alternative therapy.
Voriconazole Strong CYP3A4 inhibitors may increase levels of ivacaftor. Monitor concomitant therapy closely.

Liều Lượng & Cách Dùng : Tablet - Oral - 150mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Vertex Pharmaceuticals Incorporated

Sản phẩm biệt dược : Kalydeco

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB08820

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09916

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/51167-200-01

Wikipedia

http://en.wikipedia.org/wiki/Ivacaftor

RxList

http://www.rxlist.com/kalydeco-drug.htm

Drugs.com

http://www.drugs.com/kalydeco.html

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