| 词条 | Ledipasvir/sofosbuvir | ||||||||||||||||
| 释义 |
| IUPAC_name = | image = Ledipasvir.svg | alt = | caption = Ledipasvir | image2 =Sofosbuvir structure.svg | alt2 = | caption2 = Sofosbuvir structure | type = combo | component1 = Ledipasvir | class1 = NS5A inhibitor | component2 = Sofosbuvir | class2 = NS5B (RNA polymerase) inhibitor | tradename = Harvoni, Hepcinat-LP, others | routes_of_administration = by mouth | Drugs.com = {{Drugs.com|monograph|ledipasvir-and-sofosbuvir}} | licence_EU = yes | legal_US = Rx-only | pregnancy_US = B | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number = | ATC_prefix = J05 | ATC_suffix = AP51 | ATC_supplemental = | PubChem =72734365 | DrugBank = | UNII = | KEGG = D10578 |molecular_weight=1418.476 g/mol |chemical_formula=C71H83F3N11O15P |StdInChIKey=YWRYBUCQWKGONV-CABNZSRHSA-N |melting_point=170-225}}Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C.[1] It is a combination of ledipasvir and sofosbuvir.[1] Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1.[3] Some evidence also supports use in HCV genotype 3 and 4.[1] It is taken daily by mouth for 8–24 weeks.[1] It is generally well tolerated.[2] Common side effects include muscle pains, headache, nausea, rash, and cough.[1] It is unclear if use in pregnancy is safe for the baby.[1] Ledipasvir works by decreasing the activity of NS5A and sofosbuvir works by decreasing the activity of NS5B polymerase.[1] Ledipasvir/sofosbuvir was approved for medical use in the United States in 2014.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] The wholesale cost in the United States is about US$91,589.40 for 12 weeks as of 2016.[5] In Bangladesh this amount costs US$1,092.00.[6] Some people travel to India to get access to lower cost medication.[7] Medical usesCure rates are 94% to 99% in people infected with genotype 1 (46% of HCV cases).[8] It has also been evaluated for the treatment of infection with other hepatitis C genotypes, and has shown promising results in genotypes 3 and 4 (making up 30% and less than 22% of HCV cases respectively).[1][9][10][11][8] ResistanceNS5A mutationsMultiple mutations of HCV replicons are necessary to cause a significant effect in resistance due to multiple mechanisms of action.[12] In general, HCV genotype 1a is less resistant to mutation than genotype 1b.[13] For genotype 1b a single amino acid substitution (e.g. L31V) in the replicon had less than a 100 fold increase in resistance to the ledipasvir in Harvoni, while a two amino acid substitution had over a 1000 fold increase in resistance.[13][14] Genotype 1a had a similar but more substantial increase in resistance with each respective increase in amino acid substitution with resistance associated substitutions at K24R, M28T/V, Q30R/H/K/L, L31M, and or Y93H/N.[25] NS5A polymorphisms also have an effect on viral resistance with the most common resistance-associated amino acid substitutions detected at Q30R, Y93H or N, and L31M in patients with a rapid virological response (RVR).[25] The specific baseline NS5A resistance-associated polymorphisms observed in clinical trials were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a and L28M, A92T, and Y93H in genotype 1b.[25] Patients with multiple baseline NS5A polymorphisms tend to have higher relapse rates when using ledipasvir/sofosbuvir.[25] The difference in relapse rates between treatment naive and treatment experience groups with baseline NS5A polymorphisms ranges from 1% after a 12 week regimen and 0% after a 24 week regimen respectively.[13][25] NS5B mutationsA single amino acid substitution S282T contributes to viral resistance and decreases the activity of sofosbuvir in ledipasvir/sofosbuvir by approximately 2 to 18 fold.[13][15] Cross resistanceNo cross resistance was seen in the combination of ledipasvir and sofosbuvir in ION phase 1,2 and, 3 clinical trials as ledipasvir was fully active against sofosbuvir-resistance-associated substitutions and vice versa.[25][16] Side effectsMore than 10% of people taking ledipasvir/sofosbuvir have headaches or fatigue; rashes, nausea, diarrhea, and insomnia occur in between 1% and 10% of people taking it.[9][17] More severe reactions are connected with allergic reactions to the medications and cardiovascular problems.[18] Harvoni side effects are considered relatively mild compared to older interferon-based treatment. Drug interactionsLedipasvir/sofosbuvir is a substrate for the drug transporters P-Glycoprotein (P-gp) and breast cancer resistance protein (BCRP).[13] Intestinal absorption of these drug transporter substrates may be decreased by inducers such as rifampin and St. John's wort .[19] Patients are also advised to stay away from H2 Receptor Antagonists (H2RA) and Proton Pump Inhibitors (PPI) because they decrease the concentration of ledipasvir (it's solubility is pH-dependent and is higher under acidic conditions). Therefore it is advised to take a PPI at least two hours after ledipasvir/sofosbuvir with a dose less than or equal to 20 mg daily and H2RAs with a dose of less than or equal to 40 mg twice daily.[13][20] Ledipasvir/sofosbuvir should additionally be avoided when taking amiodarone or other drugs that lower heart rate; there is a serious risk of the heart slowing or stopping when ledipasvir/sofosbuvir is used with such drugs.[9][17] Mechanisms of actionThe most commonly associated mechanism associated with ledipasvir/sofosbuvir is the hyperphosphorylation of NS5A, a viral polymerase important in proper viral assembly and interferes with proper liver metabolism.[21] Ledipasvir/sofosbuvir inhibits the proper viral assembly by re-positioning NS5A's sub-cellular localization.[13] NS5B, a viral polymerase that can initiate RNA synthesis de novo, is also allosterically inhibited by ledipasvir/sofosbuvir.[22]NS5A and NS5B inhibitors in combination have a synergistic effect.[23] PharmacokineticsSofosbuvir is absorbed fast in the plasma with a peak concentration (Cmax) at 0.8 to 1 hour after the administered dosage and undergoes extra hepatic metabolism with 61 to 65% bound to human plasma proteins.[24][13] It is then predominantly converted to the inactive phosphate free circulating metabolite GS-331007 (eliminated 76% through renal passive filtration) which has a median peak plasma concentration at 3.5 to 4 hours after the medication is ingested.[25][26] Sofosbuvir does not appear to be affected by different levels of macronutrients when compared with fasting states.[27] Ledipasvir has a maximum concentration at 4 to 4.5 hours after ingestion and is not affected by macronutrients.[13][26] It is more than 98% protein bound and is predominantly eliminated fecally, with minimal metabolism in the liver.[26] EliminationThe median terminal half life after a dosage of ledipasvir/sofosbuvir for 90 mg of [14C]-Ledipasvir is 47 hours; for 400 mg of [14C]-Sofosbuvir it is 0.5 hours (after the initial distribution of medication in body tissue) and 27 hours (the eventual excretion of the medication).[26][28]
Note: The maximum concentration is 32% higher in healthy individuals than those infected with Hepatitis C.[26]
Note: The maximum concentration is 24% higher in healthy individuals than those infected with Hepatitis C.[26] Blood detectionAn analytical method based on LC tandem MS has been developed for the simultaneous extraction and determination of ledipasvir/sofosbuvir in human plasma using antiviral daclatasvir as an internal standard. Average extraction recoveries for sofosbuvir and ledipasvir were 91.61% and 88.93% respectively.[29] Society and cultureOne manufacturer is Gilead Sciences.[3] References1. ^1 2 {{cite journal |vauthors=Keating GM |title=Ledipasvir/Sofosbuvir: a review of its use in chronic hepatitis C |journal=Drugs |volume=75 |issue=6 |pages=675–85 |year=2015 |pmid=25837989 |doi=10.1007/s40265-015-0381-2 |url=}} {{RNA antivirals}}{{DEFAULTSORT:Ledipasvir sofosbuvir}}2. ^{{cite book|title=The selection and use of essential medicines: Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children).|date=2015|publisher=WHO|isbn=9789240694941|pages=70|url=http://apps.who.int/iris/bitstream/10665/189763/1/9789241209946_eng.pdf?ua=1|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161220085929/http://apps.who.int/iris/bitstream/10665/189763/1/9789241209946_eng.pdf?ua=1|archivedate=20 December 2016|df=}} 3. ^1 2 3 4 5 6 7 {{cite web|title=Ledipasvir and Sofosbuvir|url=https://www.drugs.com/monograph/ledipasvir-and-sofosbuvir.html|publisher=The American Society of Health-System Pharmacists|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161225214944/https://www.drugs.com/monograph/ledipasvir-and-sofosbuvir.html|archivedate=25 December 2016|df=}} 4. ^{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}} 5. ^{{cite web|title=NADAC as of 2016-12-21 {{!}} Data.Medicaid.gov|url=https://data.medicaid.gov/Drug-Prices/NADAC-as-of-2016-12-21/6ebu-k7ew|website=Centers for Medicare and Medicaid Services|accessdate=25 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161224234652/https://data.medicaid.gov/Drug-Prices/NADAC-as-of-2016-12-21/6ebu-k7ew|archivedate=24 December 2016|df=}} 6. ^{{cite book|last1=Azam|first1=Monirul|title=Intellectual Property and Public Health in the Developing World|publisher=Open Book Publishers|isbn=9781783742318|url=https://books.google.ca/books?id=iq4yDAAAQBAJ&pg=PT23|language=en|chapter=1|deadurl=no|archiveurl=https://web.archive.org/web/20161226054833/https://books.google.ca/books?id=iq4yDAAAQBAJ&pg=PT23|archivedate=2016-12-26|df=}} 7. ^{{cite news | url=http://www.fiercepharma.com/story/hep-c-drug-tourism-has-begun-patients-seek-harvoni-sovaldi-overseas/2015-06-02 | title=Hep C drug tourism has begun as patients seek Harvoni, Sovaldi overseas | work=FiercePharma | date=2015-06-02 | accessdate=2015-10-25 | deadurl=no | archiveurl=https://web.archive.org/web/20151104093803/http://www.fiercepharma.com/story/hep-c-drug-tourism-has-begun-patients-seek-harvoni-sovaldi-overseas/2015-06-02 | archivedate=2015-11-04 | df= }} 8. ^1 {{Cite journal|last=Messina|first=Jane P.|last2=Humphreys|first2=Isla|last3=Flaxman|first3=Abraham|last4=Brown|first4=Anthony|last5=Cooke|first5=Graham S.|last6=Pybus|first6=Oliver G.|last7=Barnes|first7=Eleanor|date=January 2015|title=Global distribution and prevalence of hepatitis C virus genotypes|journal=Hepatology|volume=61|issue=1|pages=77–87|doi=10.1002/hep.27259|issn=1527-3350|pmc=4303918|pmid=25069599}} 9. ^1 2 {{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205834s010lbl.pdf|publisher=FDA|title=US Label|date=June 2016|deadurl=no|archiveurl=https://web.archive.org/web/20170205102340/http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205834s010lbl.pdf|archivedate=2017-02-05|df=}}. See FDA index page for NDA 205834 {{webarchive|url=https://web.archive.org/web/20170205102255/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=205834 |date=2017-02-05 }}. 10. ^{{cite news|title=Sofosbuvir/ledipasvir effective for relapsed hep C patients|url=http://www.familypracticenews.com/news/journals/single-article/sofosbuvirledipasvir-effective-for-relapsed-hep-c-patients/61f3e868769ed6ee913673ba6638dc3e.html|agency=Family Practice News|ref=fpn}} 11. ^{{cite journal|last1=Canadian Agency for Drugs and Technologies in Health|title=Holkira (Ombitasvir/Paritaprevir/ Ritonavir with Dasabuvir) and Harvoni (Ledipasvir/Sofosbuvir) for Chronic Hepatitis C: A Review of the Clinical Evidence|journal=Rapid Response Service|date=16 January 2015|pmid=25674658|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072258/|publisher=Canadian Agency for Drugs and Technologies in Health|deadurl=no|archiveurl=https://web.archive.org/web/20171105200745/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072258/|archivedate=5 November 2017|df=}} 12. ^{{Cite journal|last=Issur|first=Moheshwarnath|last2=Götte|first2=Matthias|date=2014-11-06|title=Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding |journal=Viruses|volume=6|issue=11|pages=4227–4241|doi=10.3390/v6114227|issn=1999-4915|pmc=4246218|pmid=25384189}} 13. ^1 2 3 4 5 6 7 8 {{Cite journal|last=Gritsenko|first=Diana|last2=Hughes|first2=Gregory|date=April 2015 |title=Ledipasvir/Sofosbuvir (Harvoni): Improving Options for Hepatitis C Virus Infection |journal=Pharmacy and Therapeutics|volume=40|issue=4|pages=256–276|issn=1052-1372|pmc=4378517|pmid=25859119}} 14. ^{{Cite journal|last=Gao|first=Min|date=October 2013|title=Antiviral activity and resistance of HCV NS5A replication complex inhibitors|journal=Current Opinion in Virology|volume=3|issue=5|pages=514–520|doi=10.1016/j.coviro.2013.06.014|issn=1879-6265|pmid=23896281}} 15. ^{{Cite journal|last=Vermehren|first=Johannes|last2=Sarrazin|first2=Christoph|date=August 2012|title=The role of resistance in HCV treatment|journal=Best Practice & Research. 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Valerie|last2=Chung|first2=Raymond|title=Recent FDA approval of sofosbuvir and simeprevir. 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