Ledipasvir

Ledipasvir
Clinical data
Trade namesHarvoni (combination with sofosbuvir)
Other namesGS-5885
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability76%
Protein binding>99%
MetabolismNo cytochrome metabolism
Elimination half-life47 hrs
Identifiers
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC49H54F2N8O6
Molar mass889.018 g·mol−1
3D model (JSmol)
SMILES
  • COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
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
  • Key: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 uses

Ledipasvir 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 effects

According to clinical trials, ledipasvir/sofosbuvir has been very well tolerated with the most common side effects being fatigue and headache.[9]

Interactions

Most 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 action

Ledipasvir 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]

Cost

Similar 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

References

  1. ↑ "Ledipasvir" (PDF). United States Adopted Name.
  2. ↑ "Ledipasvir-submitted-to-FDA".
  3. ↑ "GS-5885". Gilead Sciences. Archived from the original on 2013-04-10. Retrieved 2013-03-08.
  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 Archived 2013-03-23 at the Wayback Machine. 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 Archived 2015-09-24 at the Wayback Machine. Highleyman, Liz. HIVandHepatitis.com. 4 March 2013.
  6. ↑ "Gilead Files for U.S. Approval of Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Hepatitis C". Gilead Sciences. 10 February 2014.
  7. ↑ "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". 10 October 2014. Retrieved 10 October 2014.
  8. ↑ Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. (May 2014). "Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection". The New England Journal of Medicine. 370 (20): 1889–98. doi:10.1056/NEJMoa1402454. PMID 24725239.
  9. 1 2 "PRESCRIBING INFORMATION" (PDF). www.gilead.com. Retrieved 2019-06-12.
  10. 1 2 3 "Ledipasvir-Sofosbuvir Harvoni - Treatment - Hepatitis C Online". www.hepatitisc.uw.edu.
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