Indacaterol

Các tên gọi khác (4 ) :

5-(2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl)-8-hydroxy-1H-quinolin-2-one
QAB 149
QAB-149
QAB149

Thuốc Gốc

Small Molecule

CAS: 312753-06-3

ATC: R03AC18

CTHH: C₂₄H₂₈N₂O₃

PTK: 392.4907

Indacaterol is a novel, ultra-long-acting, rapid onset β(2)-adrenoceptor agonist developed for Novartis for the once-daily management of asthma and chronic obstructive pulmonary disease. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez on November 30, 2009, and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohaler, on July 1, 2011. Indacaterol is provided as its maleate salt form. Indacaterol is also a chiral molecule but only the pure R-enantiomer is dispensed.

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/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)/t22-/m0/s1

InChI Key

InChIKey=QZZUEBNBZAPZLX-QFIPXVFZSA-N

IUPAC Name

5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1,2-dihydroquinolin-2-one

Traditional IUPAC Name

indacaterol

SMILES

CCC1=C(CC)C=C2CC(CC2=C1)NC[C@H](O)C1=C2C=CC(=O)NC2=C(O)C=C1

Độ tan chảy

195-202°C with decomposition

Độ hòa tan

7.98e-03 g/l

logP

3.26

logS

-4.7

pKa (strongest acidic)

8.51

pKa (Strongest Basic)

9.71

PSA

81.59 Å²

Refractivity

118.1 m³·mol^-1

Polarizability

44.96 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

MDDR-Like Rule

true

Dược Lực Học : Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359]

Cơ Chế Tác Dụng : Indacaterol is a novel, ultra-long-acting, rapid onset β(2)-adrenoceptor agonist developed for Novartis for the once-daily management of asthma and chronic obstructive pulmonary disease. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez on November 30, 2009, and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohaler, on July 1, 2011. Indacaterol is provided as its maleate salt form. Indacaterol is also a chiral molecule but only the pure R-enantiomer is dispensed. Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes. The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.

Dược Động Học :

▧ Absorption :
The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%.
▧ Volume of Distribution :
After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution.
▧ Protein binding :
The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
▧ Metabolism :
After oral administration of radiolabeled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. The monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide were the most prominent metabolites in serum. Other metabolites identified include a diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products. In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol.
▧ Route of Elimination :
Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose).
▧ Half Life :
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.
▧ Clearance :
Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h.

Độc Tính : The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol.

Chỉ Định : For the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Tương Tác Thuốc :

Acebutolol Beta-adrenergic antagonists, especially those that are not cardioselective, may interfere with the effect of indacaterol when administered concurrently. Beta-blockers may exacerbate bronchospasms in patients with COPD.
Amiodarone Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Amitriptyline Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Asenapine Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Atenolol Beta-adrenergic antagonists, especially those that are not cardioselective, may interfere with the effect of indacaterol when administered concurrently. Beta-blockers may exacerbate bronchospasms in patients with COPD.
Bambuterol Concomitant use with other inhaled, long acting beta2-adrenergic drugs may result in an overdose. Adverse cardiovascular effects and fatalities have been associated with excessive use of inhaled sympathomimetic drugs.
Betamethasone Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Bisoprolol Beta-adrenergic antagonists, especially those that are not cardioselective, may interfere with the effect of indacaterol when administered concurrently. Beta-blockers may exacerbate bronchospasms in patients with COPD.
Chlorthalidone Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Cyclobenzaprine Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Desipramine Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Erythromycin Strong inhibitors of CYP3A4 may increase levels of indacaterol. Monitor closely for adverse events.
Ethacrynic acid Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Formoterol Concomitant use with other inhaled, long acting beta2-adrenergic drugs may result in an overdose. Adverse cardiovascular effects and fatalities have been associated with excessive use of inhaled sympathomimetic drugs.
Furosemide Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Haloperidol Concomitant therapy with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval should be monitored closely. These drugs may potentiate the effect of adrenergic agonist on the cardiovascular system.
Hydrochlorothiazide Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Hydrocortisone Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Ketoconazole Strong CYP3A4 inhibitors increase levels of indacaterol. Consider alternate therapy.
Ondansetron Both indacaterol and ondansetron prolong the QT interval. Consider alternate therapy.
Prednisone Concomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Propranolol Beta-adrenergic antagonists, especially those that are not cardioselective, may interfere with the effect of indacaterol when administered concurrently. Beta-blockers may exacerbate bronchospasms in patients with COPD.
Ritonavir Strong inhibitors of CYP3A4 may increase levels of indacaterol. Monitor closely for adverse events.
Salmeterol Concomitant use with other inhaled, long acting beta2-adrenergic drugs may result in an overdose. Adverse cardiovascular effects and fatalities have been associated with excessive use of inhaled sympathomimetic drugs.
Verapamil Strong inhibitors of CYP3A4 may increase levels of indacaterol. Monitor closely for adverse events.

Liều Lượng & Cách Dùng : Capsule - Respiratory (inhalation) - 75 mcg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Novartis

Sản phẩm biệt dược : Arcapta
Công ty :

Sản phẩm biệt dược : Hirobriz
Công ty : Novartis

Sản phẩm biệt dược : Onbrez
Công ty :

Sản phẩm biệt dược : Onbrize

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB05039

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09318

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0078-0619-15

PharmGKB

http://www.pharmgkb.org/drug/PA165958348

Wikipedia

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

RxList

http://www.rxlist.com/arcapta-neohaler-drug.htm

Drugs.com

http://www.drugs.com/international/indacaterol.html

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