Ponatinib

Các tên gọi khác (3) :

AP 24534
AP24534
Ponatinibum

Thuốc Gốc

Small Molecule

CAS: 943319-70-8

CTHH: C₂₉H₂₇F₃N₆O

PTK: 532.5595

Ponatinib is a novel Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia. FDA approved on December 14, 2012.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₉H₂₇F₃N₆O

Phân tử khối

532.5595

Monoisotopic mass

532.219844131

InChI

InChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)

InChI Key

InChIKey=PHXJVRSECIGDHY-UHFFFAOYSA-N

IUPAC Name

3-(2-{imidazo[1,2-b]pyridazin-3-yl}ethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide

Traditional IUPAC Name

ponatinib

SMILES

CN1CCN(CC2=CC=C(NC(=O)C3=CC(C#CC4=CN=C5C=CC=NN45)=C(C)C=C3)C=C2C(F)(F)F)CC1

Độ hòa tan

2.95e-03 g/l

logP

4.97

logS

-5.3

pKa (strongest acidic)

11.36

pKa (Strongest Basic)

8.03

PSA

65.77 Å²

Refractivity

152.63 m³·mol^-1

Polarizability

55.69 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

pKa

2.77 and 7.8

Cơ Chế Tác Dụng : Ponatinib is a novel Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia. FDA approved on December 14, 2012. Ponatinib is a multi-target kinase inhibitor. Its primary cellular target is the Bcr-Abl tyrosine kinase protein which is constitutively active and promotes the progression of CML. This protein arises from the fused Bcr and Abl gene- what is commonly known as the Philadelphia chromosome. Ponatinib is unique in that it is especially useful in the treatment of resistant CML because it inhibits the tyrosine kinase activity of Abl and T315I mutant kinases. The T315I mutation confers resistance in cells as it prevents other Bcr-Abl inhibitors from binding to the Abl kinase. Other targets that ponatinib inhibits are members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. A decrease in tumour size expressing native or T315I mutant BCR-ABL have been observed in rats.

Dược Động Học :

▧ Absorption :
The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration. Food does not affect absorption of food. The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. When 45 mg of ponatinib is given to cancer patients, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL; AUC = 1253 ng•hr/mL;
▧ Volume of Distribution :
After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the steady state volume of distribution is 1223 L. Ponatinib is a weak substrate for P-gp and ABCG2.
▧ Protein binding :
> 99% bound to plasma proteins.
▧ Metabolism :
At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.
▧ Route of Elimination :
Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.
▧ Half Life :
After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the terminal elimination half-life is 24 hours (range of 12 - 66 hours).

Độc Tính : The most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Chỉ Định : Ponatinib is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Tương Tác Thuốc :

Boceprevir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Carbamazepine Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Carbamazepine Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Clarithromycin Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Conivaptan Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Indinavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Itraconazole Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Ketoconazole Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Lopinavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Nefazodone Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Nelfinavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Phenytoin Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Phenytoin Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Posaconazole Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Rifampicin Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Rifampicin Strong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
Ritonavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Ritonavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Saquinavir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Telaprevir Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Telithromycin Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Voriconazole Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.

Liều Lượng & Cách Dùng : Tablet - Oral - 15 mg, 45 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Ariad

Sản phẩm biệt dược : Iclusig

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB08901

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09950

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/76189-534-30

Wikipedia

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

Drugs.com

http://www.drugs.com/mtm/ponatinib.html

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