Telaprevir

Các tên gọi khác (5 ) :

(1S,3AR,6as)-(2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino)oxoacetyl)butyl)octahydrocyclopenta(c)pyrrole-1-carboxamide
Incivek
MP-424
VX 950
VX-950

Thuốc Gốc

Small Molecule

CAS: 402957-28-2

ATC: J05AE11

CTHH: C₃₆H₅₃N₇O₆

PTK: 679.8493

Telaprevir (VX-950) is a highly selective and potent inhibitor of the HCV NS3-4A serine protease. It is a member of a class of antiviral drugs known as protease inhibitors and is the first hepatitis C drug that has demonstrated activity in patients who have failed prior therapy. On April 28, 2011, the FDA Antiviral Drugs Advisory Committee voted 18-0 to recommend approval telaprevir for people with genotype 1 chronic hepatitis C and was approved in the U.S. in May, 2011.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₃₆H₅₃N₇O₆

Phân tử khối

679.8493

Monoisotopic mass

679.405732463

InChI

InChI=1S/C36H53N7O6/c1-5-10-25(29(44)34(48)39-23-15-16-23)40-33(47)28-24-14-9-13-22(24)20-43(28)35(49)30(36(2,3)4)42-32(46)27(21-11-7-6-8-12-21)41-31(45)26-19-37-17-18-38-26/h17-19,21-25,27-28,30H,5-16,20H2,1-4H3,(H,39,48)(H,40,47)(H,41,45)(H,42,46)/t22-,24-,25-,27-,28-,30+/m0/s1

InChI Key

InChIKey=BBAWEDCPNXPBQM-GDEBMMAJSA-N

IUPAC Name

(3S)-3-{[(1S,3aR,6aS)-2-[(2S)-2-[(2S)-2-cyclohexyl-2-(pyrazin-2-ylformamido)acetamido]-3,3-dimethylbutanoyl]-octahydrocyclopenta[c]pyrrol-1-yl]formamido}-N-cyclopropyl-2-oxohexanamide

Traditional IUPAC Name

(3S)-3-{[(1S,3aR,6aS)-2-[(2S)-2-[(2S)-2-cyclohexyl-2-(pyrazin-2-ylformamido)acetamido]-3,3-dimethylbutanoyl]-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido}-N-cyclopropyl-2-oxohexanamide

SMILES

[H][C@@]12CCC[C@]1([H])[C@H](N(C2)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)C1=NC=CN=C1)C1CCCCC1)C(C)(C)C)C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1

Độ hòa tan

0.0047 mg/mL

logP

2.58

logS

-4.3

pKa (strongest acidic)

11.86

pKa (Strongest Basic)

-0.69

PSA

179.56 Å²

Refractivity

180.04 m³·mol^-1

Polarizability

74.37 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

Dược Lực Học : Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.

Cơ Chế Tác Dụng : Telaprevir (VX-950) is a highly selective and potent inhibitor of the HCV NS3-4A serine protease. It is a member of a class of antiviral drugs known as protease inhibitors and is the first hepatitis C drug that has demonstrated activity in patients who have failed prior therapy. On April 28, 2011, the FDA Antiviral Drugs Advisory Committee voted 18-0 to recommend approval telaprevir for people with genotype 1 chronic hepatitis C and was approved in the U.S. in May, 2011. Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. It belongs to the chemical class of alpha-ketoamids and binds to NS3/4A in a covalent but reversible manner.

Dược Động Học :

▧ Absorption :
Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone. Dissolution of telaprevir is not dependent by pH.
▧ Volume of Distribution :
Apparent volume of distribution (Vd/F) = 252 L. This large volume of distribution suggests extensive penetration into tissues.
▧ Protein binding :
59% to 76% and binds to alpha 1-acid glycoprotein and albumin in a concentration dependent manner.
▧ Metabolism :
Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major CYP isoform responsible for telaprevir metabolism. However, non-CYP mediated metabolism likely plays a role after multiple dosing of telaprevir.
▧ Route of Elimination :
Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively.
▧ Half Life :
The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.
▧ Clearance :
After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 L/h with an inter-individual variability of 27.2%.

Độc Tính : The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with telaprevir alone. In that study, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting. The two most common adverse events that caused the discontinuation of treatment are anemia and rash.

Chỉ Định : Treating chronic hepatitis C virus (genotype 1) infection in patients with compensated liver (due to liver diseases like cirrhosis) that are treatment naive or have failed therapy with interferons (either null or partial responders and treatment relapsers).

Tương Tác Thuốc :

Alfuzosin Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Alprazolam Telaprevir inhibits systemic metabolism of alprazolam and dose adjustment may be necessary.
Amlodipine Telaprevir inhibits the metabolism of amlodipine and concomitant therapy is contraindicated.
Atorvastatin Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Cisapride Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Clobetasol propionate Corticosteroids such as clobetasol may decrease the serum concentration of telaprevir. Telaprevir may increase the serum concentration of corticosteroids. Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives, and if such a combination is necessary, use extra caution, monitoring patients for excessive systemic steroid effects as well as for diminished telaprevir effects.
Clocortolone Corticosteroids such as clocortolone may decrease the serum concentration of telaprevir. Telaprevir may increase the serum concentration of Corticosteroids. Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives, and if such a combination is necessary, use extra caution, monitoring patients for excessive systemic steroid effects as well as for diminished telaprevir effects.
Conivaptan Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Cyclosporine Telaprevir increases levels by affecting CYP3A4 metabolism. Must monitor levels closely with concomitant therapy.
Digoxin Telaprevir is a substrate of p-glycoprotein and thus increases the AUC and Cmax of digoxin. This indicates an increased absorption of digoxin. Lowest dose of digoxin should be used first and levels be closely monitored.
Dihydroergotamine Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Efavirenz Inducers of CYP3A enzymes will decrease telaprevir levels.
Ergotamine Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Escitalopram Telaprevir decreases Cmax, Cmin, and AUC of escitalopram however the mechanism of this interaction is unknown. Concomitant therapy may call for dose adjustment.
Etravirine Telaprevir, when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to monitor telaprevir therapy closely.
Ketoconazole Strong CYP3A4 inhibitors increase exposure of telaprevir.
Lomitapide Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Lovastatin Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Methadone Telaprevir decreases exposure of methane by 30% however opioid withdrawal was not observed in patients.
Midazolam Telaprevir increases AUC and Cmax of oral midazolam by approximately 9-fold and 3-fold respectively.
Nelfinavir Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Pimozide Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Ponatinib Strong CYP3A4 inhibitors may increase levels of ponatinib. Monitor concomitant therapy closely.
Raltegravir Telaprevir increases the exposure of raltegravir by up to 31% but this interaction is considered as not clinically relevant.
Rifampicin Strong CYP3A4 inducers will decrease levels of telaprevir. Concomitant therapy is contraindicated.
Ritonavir Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Simvastatin Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Tacrolimus Telaprevir increases levels by affecting CYP3A4 metabolism. Must monitor levels closely with concomitant therapy.
Tadalafil Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
Triazolam Telaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.

Liều Lượng & Cách Dùng : Tablet, film coated - Oral - 375mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Johnson & Johnson

Sản phẩm biệt dược : Incivek

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB05521

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=3010818

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09012

ChemSpider

http://www.chemspider.com/Chemical-Structure.2279948.html

BindingDB

http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50212208

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/51167-100-01

PharmGKB

http://www.pharmgkb.org/drug/PA165958354

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/cdi/telaprevir.html

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