| 词条 | Ledipasvir |
| 释义 |
| drug_name = | IUPAC_name = Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S,2S,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3H-benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1-oxobutan-2-yl]carbamate | image = Ledipasvir.svg | alt = | caption = | tradename = Harvoni (combination with sofosbuvir) | Drugs.com = | MedlinePlus = | pregnancy_AU = | pregnancy_US = | pregnancy_category= | licence_EU = yes | legal_AU = | legal_CA = | legal_UK = | legal_US = Rx-only | legal_status = | routes_of_administration = by mouth | bioavailability = 76% | protein_bound = >99% | metabolism = No cytochrome metabolism | elimination_half-life = 47 hrs | excretion = | CAS_number = 1256388-51-8 | ATCvet = | ATC_prefix = J05 | ATC_suffix = AP51 | ATC_supplemental = (combination with sofosbuvir) | PubChem = 67505836 | DrugBank = DB09027 | ChemSpiderID = 29271894 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 85089 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D10442 | UNII = 013TE6E4WV | synonyms = GS-5885 | C=49 | H=54 | F=2 | N=8 | O=6 | molecular_weight = 889.00 g/mol | smiles = CC(C)[C@@H](C(=O)N1CC2(CC2)C[C@H]1C3=NC=C(N3)C4=CC5=C(C=C4)C6=C(C5(F)F)C=C(C=C6)C7=CC8=C(C=C7)N=C(N8)[C@@H]9[C@H]1CC[C@H](C1)N9C(=O)[C@H](C(C)C)NC(=O)OC)NC(=O)OC | StdInChI = 1S/C49H54F2N8O6/c1-24(2)39(56-46(62)64-5)44(60)58-23-48(15-16-48)21-38(58)42-52-22-37(55-42)28-9-13-32-31-12-8-26(18-33(31)49(50,51)34(32)19-28)27-10-14-35-36(20-27)54-43(53-35)41-29-7-11-30(17-29)59(41)45(61)40(25(3)4)57-47(63)65-6/h8-10,12-14,18-20,22,24-25,29-30,38-41H,7,11,15-17,21,23H2,1-6H3,(H,52,55)(H,53,54)(H,56,62)(H,57,63)/t29-,30+,38-,39-,40-,41-/m0/s1 | StdInChIKey = VRTWBAAJJOHBQU-KMWAZVGDSA-N }} Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences.[1] After completing Phase III clinical trials, on February 10, 2014 Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C.[2][3] The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin. Ledipasvir is an inhibitor of NS5A, a hepatitis C virus protein. Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of the nucleotide analog inhibitor sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[4][5] The sofosbuvir/ledipasvir coformulation is being tested with and without ribavirin. In February 2014 Gilead filed for United States Food and Drug Administration (FDA) approval of ledipasvir/sofosbuvir oral treatment, without interferon and ribavirin.[6] On 10 October 2014 the FDA approved the combination product ledipasvir/sofosbuvir called Harvoni.[7] Medical usesLedipasvir is most commonly used in combination with sofosbuvir for treatment in chronic hepatitis C genotype 1 patients. This drug has been tested and shown efficacy in treatment-naive and treatment experienced patients.[8] Adverse effectsAccording to clinical trials, ledipasvir/sofosbuvir has been very well tolerated with the most common side effects being fatigue and headache.[9] InteractionsMost drug-drug interactions with Harvoni involve Pgp-inducers such as St. John’s wort or rifampicin. Concomitant use will decrease the blood concentration of Harvoni and thus, have reduced therapeutic effects.[9] Mechanism of actionLedipasvir inhibits an important viral phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion.[10] Sofosbuvir, on the other hand, is metabolized to a uridine triphosphate mimic, which acts as a RNA chain terminator when incorporated into RNA by NS5B polymerase.[10] CostSimilar to sofosbuvir, the cost of Harvoni has been a controversial topic. It costs $1,125 per pill in the US, translating to $63,000 for an 8-week treatment course, $94,500 for a 12-week treatment course, or $189,000 for a 24-week treatment course. Gilead justifies the cost by outweighing the benefit of curing hepatitis C over the cost of spending double on liver transplants or temporarily treating liver diseases. Gilead has provided a ledipasvir/sofosbuvir assistance program for eligible underserved or underinsured hepatitis C patients who cannot afford the costs of treatment.[10] In July 2015 Gilead modified the eligibility criteria to receive Support Path benefits for HCV patients in the United States. See also
References1. ^{{cite web | url = http://www.ama-assn.org/resources/doc/usan/ledipasvir.pdf | title = Ledipasvir | publisher = United States Adopted Name}} {{RNA antivirals}}{{portal bar|Pharmacy and pharmacology|Medicine}}2. ^{{cite web | url = http://www.gilead.com/news/press-releases/2014/2/gilead-files-for-us-approval-of-ledipasvirsofosbuvir-fixeddose-combination-tablet-for-genotype-1-hepatitis-c#sthash.nk1apkTf.dpuf. | title = Ledipasvir-submitted-to-FDA}} 3. ^{{cite web | url = http://www.gilead.com/pipeline | title = GS-5885 | publisher = Gilead Sciences}} 4. ^ELECTRON: 100% Suppression of Viral Load through 4 Weeks’ Post-treatment for Sofosbuvir + Ledipasvir (GS-5885) + Ribavirin for 12 Weeks in Treatment-naïve and -experienced Hepatitis C Virus GT 1 Patients {{webarchive|url=https://web.archive.org/web/20130323091846/http://www.retroconference.org/2013b/Abstracts/47869.htm |date=2013-03-23 }}. Gane, Edward et al. 20th Conference on Retroviruses and Opportunistic Infections. March 3–6, 2013. Abstract 41LB. 5. ^CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, Liz. HIVandHepatitis.com. 4 March 2013. 6. ^{{cite web | url = http://www.gilead.com/news/press-releases/2014/2/gilead-files-for-us-approval-of-ledipasvirsofosbuvir-fixeddose-combination-tablet-for-genotype-1-hepatitis-c | title = Gilead Files for U.S. Approval of Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Hepatitis C | publisher = Gilead Sciences | date = 10 February 2014}} 7. ^{{cite web|url=http://www.gilead.com/news/press-releases/2014/10/us-food-and-drug-administration-approves-gileads-harvoni-ledipasvirsofosbuvir-the-first-oncedaily-single-tablet-regimen-for-the-treatment-of-genotype-1-chronic-hepatitis-c|title=U.S. Food and Drug Administration Approves Gilead’s Harvoni (Ledipasvir/Sofosbuvir), the First Once-Daily Single Tablet Regimen for the Treatment of Genotype 1 Chronic Hepatitis C |date=10 October 2014|accessdate=10 October 2014}} 8. ^{{Cite journal | pmid = 24725239| year = 2014| author1 = Afdhal| first1 = N| title = Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection| journal = New England Journal of Medicine| volume = 370| issue = 20| pages = 1889–98| last2 = Zeuzem| first2 = S| last3 = Kwo| first3 = P| last4 = Chojkier| first4 = M| last5 = Gitlin| first5 = N| last6 = Puoti| first6 = M| last7 = Romero-Gomez| first7 = M| last8 = Zarski| first8 = J. P.| last9 = Agarwal| first9 = K| last10 = Buggisch| first10 = P| last11 = Foster| first11 = G. R.| last12 = Bräu| first12 = N| last13 = Buti| first13 = M| last14 = Jacobson| first14 = I. M.| last15 = Subramanian| first15 = G. M.| last16 = Ding| first16 = X| last17 = Mo| first17 = H| last18 = Yang| first18 = J. C.| last19 = Pang| first19 = P. S.| last20 = Symonds| first20 = W. T.| last21 = McHutchison| first21 = J. G.| last22 = Muir| first22 = A. J.| last23 = Mangia| first23 = A| last24 = Marcellin| first24 = P| last25 = Ion-1| first25 = Investigators| doi = 10.1056/NEJMoa1402454}} 9. ^1 http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf 10. ^1 2 http://www.hepatitisc.uw.edu/page/treatment/drugs/ledipasvir-sofosbuvir 8 : NS5A inhibitors|Fluorenes|Carbamates|Benzimidazoles|Cyclopropanes|Imidazoles|Breakthrough therapy|World Health Organization essential medicines |
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