Eltrombopag

Các tên gọi khác (3) :

Eltrombopag
Eltrombopagum
Promacta

thrombopoietic agents

Thuốc Gốc

Small Molecule

CAS: 496775-61-2

ATC: B02BX05

CTHH: C₂₅H₂₂N₄O₄

PTK: 442.4666

Eltrombopag is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. ITP is a condition that may cause unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Eltrombopag has also been recently approved (late 2012) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₅H₂₂N₄O₄

Phân tử khối

442.4666

Monoisotopic mass

442.164105212

InChI

InChI=1S/C25H22N4O4/c1-14-10-11-19(12-15(14)2)29-24(31)22(16(3)28-29)27-26-21-9-5-8-20(23(21)30)17-6-4-7-18(13-17)25(32)33/h4-13,26,30H,1-3H3,(H,32,33)/b27-22-

InChI Key

InChIKey=XDXWLKQMMKQXPV-QYQHSDTDSA-N

IUPAC Name

3-(3-{2-[(4Z)-1-(3,4-dimethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1-yl}-2-hydroxyphenyl)benzoic acid

Traditional IUPAC Name

3-(3-{2-[(4Z)-1-(3,4-dimethylphenyl)-3-methyl-5-oxopyrazol-4-ylidene]hydrazin-1-yl}-2-hydroxyphenyl)benzoic acid

SMILES

CC1=NN(C(=O)\C1=N/NC1=C(O)C(=CC=C1)C1=CC=CC(=C1)C(O)=O)C1=CC=C(C)C(C)=C1

Độ hòa tan

Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.

logP

6.03

logS

-4.6

pKa (strongest acidic)

3.99

pKa (Strongest Basic)

0.17

PSA

114.59 Å²

Refractivity

126.48 m³·mol^-1

Polarizability

47.64 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-1

Number of Rings

Bioavailability

Cơ Chế Tác Dụng : Eltrombopag is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. ITP is a condition that may cause unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Eltrombopag has also been recently approved (late 2012) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work.

Dược Động Học :

▧ Absorption :
Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%.
▧ Volume of Distribution :
Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.
▧ Protein binding :
Eltrombopag is highly protein bound (>99%).
▧ Metabolism :
Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
▧ Route of Elimination :
Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted.
▧ Half Life :
About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura.

Độc Tính : Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation).

Chỉ Định : Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction.

Tương Tác Thuốc :

Acetaminophen Eltrombopag increases acetaminophen levels via decreasing metabolism. UDP-glucuronosyltransferase inhibition with unclear significance.
Acetylsalicylic acid Decreases metabolism, will increase effect/level of eltrombopag.
Aluminum hydroxide Decreases levels of eltrombopag by GI absorption inhibition.
Amiodarone Affects hepatic enzyme CYP2C9/10 metabolism, increases effect/level of eltrombopag.
Amobarbital Affects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Atazanavir Decreases metabolism, will increase effect/level of eltrombopag. UDP-glucuronosyltransferase inhibition.
Atorvastatin Eltrombopag increases levels of Atorvastatin via metabolism decrease.
Bromfenac Eltrombopag increases levels of Bromfenac via metabolism decrease.
Butabarbital Affects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Butalbital Affects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Calcium Acetate Calcium Salts such as calcium acetate may decrease the serum concentration of Eltrombopag. Separate administration of eltrombopag and any polyvalent cation (e.g., calcium-containing products) by at least 4 hours.
Calcium carbonate Decreases levels of eltrombopag by GI absorption inhibition.
Calcium Chloride Calcium salts such as calcium chloride may decrease the serum concentration of eltrombopag. Separate administration of eltrombopag and any polyvalent cation (e.g., calcium-containing products) by at least 4 hours.
Carbamazepine Affects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Celecoxib Eltrombopag increases levels of Celecoxib via metabolism decrease.
Cimetidine Affects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Ciprofloxacin Affects hepatic CYP1A2 metabolism, will increase effect/level of eltrombopag.
Citric Acid Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Diclofenac Eltrombopag increases levels of Diclofenac via metabolism decrease. UDP-glucuronosyltransferase inhibition.
Diflunisal Eltrombopag increases levels of Diflunisal via metabolism decrease.
Diltiazem Affects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Efavirenz Affects hepatic enzyme CYP2C9/10 metabolism and may increase the level of eltrombopag.
Enoxacin Affects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
Erythromycin Affects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Ethinyl Estradiol Affects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Etodolac Increases levels of Etodolac via metabolism decrease. UDP-glucuronosyltransferase inhibition.
Fenoprofen Increases levels of Fenoprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition.
Fentanyl Increases levels of Fentanyl via metabolism decrease. UDP-glucuronosyltransferase inhibition.
Flurbiprofen Increases levels of Flurbiprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition.
Fluvastatin Increases levels of Fluvastatin via metabolism decrease. OATP transporter protein inhibition.
Fluvoxamine Affects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
Fluvoxamine Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
Grepafloxacin Affects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
Hydrocodone Increases levels of Hydrocodone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Hydromorphone Increases levels of Hydromorphone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Ibuprofen Increases levels of Ibuprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Indomethacin Increases levels of Indomethacin via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Iron Dextran Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Iron sucrose Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Isoniazid Affects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Ketoprofen Increases levels of Ketoprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Ketorolac Increases levels of Ketorolac via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Leflunomide Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
Levorphanol Increases levels of Levorphanol via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Magnesium Sulfate Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Meclofenamic acid Increases levels of Meclofenamic acid via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Mefenamic acid Increases levels of Mefenamic acid via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Meloxicam Increases levels of Meloxicam via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Methadone Increases levels of Methadone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Methotrexate Increases levels of Methotrexate via metabolism decrease. OATP transporter protein inhibition.
Mexiletine Affects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Miconazole Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
Morphine Eltrombopag increases Morphine levels via decreasing metabolism. UDP-glucuronosyltransferase inhibition with unclear significance.
Pethidine Increases levels of Meperidine via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Selenium Sulfide Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Sodium bicarbonate Levels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Tretinoin The moderate CYP2C8 inhibitor, Eltrombopag, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Eltrombopag is initiated, discontinued or dose changed.
Valproic Acid Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
Valsartan Eltrombopag may increase the therapeutic and/or toxic effects of Valsartan. Increased Valsartan serum concentrations may be caused by inhibition of hepatic uptake and decreased metabolism. Consider dose modification, alternate therapy or monitor for changes in the therapeutic and toxic effects of Valsartan if Eltrombopag is initiated, discontinued or dose changed.
Zileuton Affects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.

Liều Lượng & Cách Dùng : Tablet, coated - Oral - 100 mg (green)
Tablet, coated - Oral - 12.5 mg (white)
Tablet, coated - Oral - 25 mg (orange)
Tablet, coated - Oral - 50 mg (blue)
Tablet, coated - Oral - 75 mg (pink)

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : GlaxoSmithKline

Sản phẩm biệt dược : Promacta
Công ty : GlaxoSmithKline

Sản phẩm biệt dược : Revolade

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06210

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D03978

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0007-4640-13

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/ppa/eltrombopag.html

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