Ledipasvir
Identification
- Summary
Ledipasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.
- Brand Names
- Harvoni
- Generic Name
- Ledipasvir
- DrugBank Accession Number
- DB09027
- Background
Ledipasvir is a direct acting antiviral (DAA) medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 9. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as ledipasvir. More specifically, ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) Non-Structural Protein 5A (NS5A), which is required for viral RNA replication and assembly of HCV virions. Although its exact mechanism of action is unknown, it is postulated to prevent hyperphosphorylation of NS5A which is required for viral protein production. It is effective against genotypes 1a, 1b, 4a, and 5a and with a lesser activity against genotypes 2a and 3a of HCV. Ledipasvir and other direct acting antivirals are very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance 8. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure.
In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend ledipasvir as a first line therapy option in combination with sofosbuvir for the treatment of HCV genotypes 1a, 1b, 4, 5, and 6 9. Treatment with ledipasvir is used with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 6. Treatment with direct acting antivirals such as ledipasvir is associated with very minimal side effects, with the most common being headache and fatigue Label. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects 7.
Since 2014, ledipasvir has been available as a fixed dose combination product with sofosbuvir (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without ribavirin depending on the level of liver damage or cirrhosis Label. When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment Label. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV 5.
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 888.9999
Monoisotopic: 888.41343791 - Chemical Formula
- C49H54F2N8O6
- Synonyms
- Ledipasvir
- Lédipasvir
- Ledipasvirum
- External IDs
- GS 5885
- GS-5885
- GS5885
- WHO 9796
Pharmacology
- Indication
When used in combination with the antiviral medication sofosbuvir, ledipasvir is indicated for the treatment of treatment of chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years of age and older with the following conditions:10
- Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
- Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin.
- Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin.
Its use has also proven successful in the treatment of HCV in patients co-infected with HIV 5.
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- Contraindications & Blackbox Warnings
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- Pharmacodynamics
Ledipasvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).
At a dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent Label.
- Mechanism of action
Ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) NS5A protein required for viral RNA replication and assembly of HCV virions. Although its exact mechanism of action is unknown, it is postulated to prevent hyperphosphorylation of NS5A which is required for viral production.
Target Actions Organism ANonstructural protein 5A inhibitorHepatitis C Virus - Absorption
When given orally, ledipasvir reaches its maximum plasma concentration in about 4 to 4.5 hours with a maximum concentration (Cmax) of 323 ng/mL Label.
- Volume of distribution
Not Available
- Protein binding
Ledipasvir is >99.8% bound to human plasma proteins Label.
- Metabolism
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (>98%). Unchanged ledipasvir is the major species present in feces Label.
- Route of elimination
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%) Label.
- Half-life
The median terminal half-life of ledipasvir is 47 hours Label.
- Clearance
Not Available
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
There is very little toxicity associated with the use of ledipasvir in combination products. The most common adverse reactions are headache and fatigue.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Ledipasvir. Abrocitinib The serum concentration of Ledipasvir can be increased when it is combined with Abrocitinib. Aceclofenac Aceclofenac may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Ledipasvir which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Aclidinium Aclidinium may decrease the excretion rate of Ledipasvir which could result in a higher serum level. Acrivastine Ledipasvir may decrease the excretion rate of Acrivastine which could result in a higher serum level. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- Avoid St. John's Wort. This herb induces PGP and may reduce the serum concentration of ledipasvir.
- Take separate from antacids. Take at least 4 hours before or after antacids.
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Harvoni Ledipasvir (45 mg/1) + Sofosbuvir (200 mg/1) Pellet Oral Gilead Sciences, Inc 2019-08-28 Not applicable US Harvoni Ledipasvir (45 mg) + Sofosbuvir (200 mg) Tablet Oral Gilead Sciences Ireland Uc 2020-12-22 Not applicable EU Harvoni Ledipasvir (45 mg/1) + Sofosbuvir (200 mg/1) Tablet, film coated Oral Gilead Sciences, Inc 2019-08-28 Not applicable US Harvoni Ledipasvir (90 mg) + Sofosbuvir (400 mg) Tablet, film coated Oral Gilead Sciences Ireland Uc 2016-09-08 Not applicable EU Harvoni Ledipasvir (33.75 mg) + Sofosbuvir (150 mg) Pellet Oral Gilead Sciences Ireland Uc 2020-12-22 Not applicable EU Harvoni Ledipasvir (90 mg/1) + Sofosbuvir (400 mg/1) Tablet, film coated Oral Gilead Sciences, Inc 2014-10-10 Not applicable US Harvoni Ledipasvir (90 mg) + Sofosbuvir (400 mg) Tablet, film coated Oral Gilead Sciences Ireland Uc 2016-09-08 Not applicable EU Harvoni Ledipasvir (90 mg) + Sofosbuvir (400 mg) Tablet Oral Gilead Sciences 2014-10-16 Not applicable Canada Harvoni Ledipasvir (33.75 mg/1) + Sofosbuvir (150 mg/1) Pellet Oral Gilead Sciences, Inc 2019-08-28 Not applicable US Harvoni Ledipasvir (45 mg) + Sofosbuvir (200 mg) Tablet, film coated Oral Gilead Sciences Ireland Uc 2020-12-22 Not applicable EU
Categories
- ATC Codes
- J05AP51 — Sofosbuvir and ledipasvir
- Drug Categories
- Anti-Infective Agents
- Antiinfectives for Systemic Use
- Antiviral Agents
- Antivirals for Systemic Use
- Antivirals for treatment of HCV infections
- BCRP/ABCG2 Inhibitors
- Direct Acting Antivirals
- Drugs that are Mainly Renally Excreted
- Hepatitis C Virus NS5A Inhibitor
- Heterocyclic Compounds, Fused-Ring
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Treatments for Hepatitis C
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as fluorenes. These are compounds containing a fluorene moiety, which consists of two benzene rings connected through either a cyclopentane, cyclopentene, or cyclopenta-1,3-diene.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Fluorenes
- Sub Class
- Not Available
- Direct Parent
- Fluorenes
- Alternative Parents
- Valine and derivatives / Alpha amino acid amides / Benzimidazoles / N-acylpiperidines / N-acylpyrrolidines / Tertiary carboxylic acid amides / Heteroaromatic compounds / Methylcarbamates / Imidazoles / Organic carbonic acids and derivatives show 8 more
- Substituents
- Alkyl fluoride / Alkyl halide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzimidazole / Carbamic acid ester / Carbonic acid derivative show 23 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- organofluorine compound, carbamate ester, imidazoles, N-acylpyrrolidine, bridged compound, ring assembly, fluorenes, carboxamide, L-valine derivative, benzimidazole, azaspiro compound (CHEBI:85089)
- Affected organisms
- Hepatitis C Virus
Chemical Identifiers
- UNII
- 013TE6E4WV
- CAS number
- 1256388-51-8
- InChI Key
- VRTWBAAJJOHBQU-KMWAZVGDSA-N
- InChI
- InChI=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
- IUPAC Name
- methyl N-[(2S)-1-[(6S)-6-[4-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1H-1,3-benzodiazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1-oxobutan-2-yl]carbamate
- SMILES
- COC(=O)N[C@@H](C(C)C)C(=O)N1CC2(CC2)C[C@H]1C1=NC(=CN1)C1=CC=C2C3=CC=C(C=C3C(F)(F)C2=C1)C1=CC=C2NC(=NC2=C1)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)[C@@H](NC(=O)OC)C(C)C
References
- Synthesis Reference
Henderson JA, Bilimoria D, Bubenik M, Cadilhac C, Cottrell KM, Denis F, Dietrich E, Ewing N, Falardeau G, Giroux S, L'Heureux L, Liu B, Mani N, Morris M, Nicolas O, Pereira OZ, Poisson C, Reddy TJ, Selliah S, Shawgo RS, Vaillancourt L, Wang J, Xu J, Chauret N, Berlioz-Seux F, Chan LC, Das SK, Grillot AL, Bennani YL, Maxwell JP: Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores. Bioorg Med Chem Lett. 2015 Feb 15;25(4):948-51. doi: 10.1016/j.bmcl.2014.12.042. Epub 2014 Dec 22. Pubmed
- General References
- Kumari R, Nguyen MH: Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1. Expert Opin Pharmacother. 2015 Apr;16(5):739-48. doi: 10.1517/14656566.2015.1013938. Epub 2015 Feb 13. [Article]
- Younossi ZM, Stepanova M, Marcellin P, Afdhal N, Kowdley KV, Zeuzem S, Hunt SL: Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: Results from the ION-1, -2, and -3 clinical trials. Hepatology. 2015 Jun;61(6):1798-808. doi: 10.1002/hep.27724. Epub 2015 Mar 18. [Article]
- Waheed Y: Ledipasvir and sofosbuvir: Interferon free therapy for hepatitis C virus genotype 1 infection. World J Virol. 2015 Feb 12;4(1):33-5. doi: 10.5501/wjv.v4.i1.33. [Article]
- Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, Bon D, Silk R, Gross C, Price A, Sajadi M, Sidharthan S, Sims Z, Herrmann E, Hogan J, Teferi G, Talwani R, Proschan M, Jenkins V, Kleiner DE, Wood BJ, Subramanian GM, Pang PS, McHutchison JG, Polis MA, Fauci AS, Masur H, Kottilil S: Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015 Mar 24-31;313(12):1232-9. doi: 10.1001/jama.2015.1373. [Article]
- Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, Marks K, Luetkemeyer A, Baden RP, Sax PE, Gane E, Santana-Bagur J, Stamm LM, Yang JC, German P, Dvory-Sobol H, Ni L, Pang PS, McHutchison JG, Stedman CA, Morales-Ramirez JO, Brau N, Jayaweera D, Colson AE, Tebas P, Wong DK, Dieterich D, Sulkowski M: Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015 Aug 20;373(8):705-13. doi: 10.1056/NEJMoa1501315. Epub 2015 Jul 21. [Article]
- Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [Article]
- Dusheiko G: Side effects of alpha interferon in chronic hepatitis C. Hepatology. 1997 Sep;26(3 Suppl 1):112S-121S. [Article]
- Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 May 12. doi: 10.1007/s40265-017-0753-x. [Article]
- American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
- FDA Approved Drug Products: Harvoni (Ledipasvir and Sofosbuvir) tablets or pellets for oral use [Link]
- External Links
- KEGG Drug
- D10442
- PubChem Compound
- 67505836
- PubChem Substance
- 310264981
- ChemSpider
- 29271894
- 1591922
- ChEBI
- 85089
- ChEMBL
- CHEMBL2374220
- ZINC
- ZINC000150338819
- PharmGKB
- PA166128166
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ledipasvir
- FDA label
- Download (486 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Basic Science Cardiovascular Disease (CVD) / Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections 1 4 Completed Other Coinfection, HIV / Hepatitis C Virus (HCV) Infection 1 4 Completed Treatment Beta Thalassaemia / Hepatitis C Virus (HCV) Infection 1 4 Completed Treatment Chronic Hepatitis C Virus (HCV) Infection 3 4 Completed Treatment Chronic Hepatitis C Virus (HCV) Infection / Chronic Obstructive Pulmonary Disease (COPD) / Heart Failure / Interstitial Lung Disease 1 4 Completed Treatment Cirrhosis of the Liver / Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections 1 4 Completed Treatment Coronavirus Disease 2019 (COVID‑19) / COVID 1 4 Completed Treatment Genotype 1 Hepatitis C Virus 1 4 Completed Treatment Hepatitis C Infection With HIV Co-Infection 1 4 Completed Treatment Hepatitis C Virus (HCV) Infection 4
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule Oral Pellet Oral Tablet Oral Tablet, coated Oral Tablet, film coated Oral Tablet, film coated Oral 90 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8841278 Yes 2014-09-23 2030-11-12 US US7964580 Yes 2011-06-21 2029-09-26 US US8334270 Yes 2012-12-18 2028-09-21 US US8822430 Yes 2014-09-02 2030-11-12 US US8633309 Yes 2014-01-21 2029-09-26 US US8273341 Yes 2012-09-25 2030-11-12 US US8618076 Yes 2013-12-31 2031-06-11 US US8735372 Yes 2014-05-27 2028-09-21 US US8580765 Yes 2013-11-12 2028-09-21 US US8889159 Yes 2014-11-18 2029-09-26 US US9085573 Yes 2015-07-21 2028-09-21 US US9284342 Yes 2016-03-15 2031-03-13 US US8088368 Yes 2012-01-03 2030-11-12 US US9393256 Yes 2016-07-19 2033-03-14 US US9511056 Yes 2016-12-06 2030-11-12 US US10039779 Yes 2018-08-07 2034-07-30 US US10456414 No 2019-10-29 2032-09-14 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 3.8 FDA Label pKa pka1 = 4.0, pka2 = 5.0 FDA Label - Predicted Properties
Property Value Source Water Solubility 0.00388 mg/mL ALOGPS logP 5.98 ALOGPS logP 7.18 Chemaxon logS -5.4 ALOGPS pKa (Strongest Acidic) 11.33 Chemaxon pKa (Strongest Basic) 5.29 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 174.64 Å2 Chemaxon Rotatable Bond Count 12 Chemaxon Refractivity 235.47 m3·mol-1 Chemaxon Polarizability 97.49 Å3 Chemaxon Number of Rings 10 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets

- Kind
- Protein
- Organism
- Hepatitis C Virus
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- Not Available
- Gene Name
- NS5A
- Uniprot ID
- Q5L478
- Uniprot Name
- Nonstructural protein 5A
- Molecular Weight
- 48598.34 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateTransporter
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Transporter
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
Drug created at November 26, 2014 23:19 / Updated at April 01, 2022 19:23