Ledipasvir/sofosbuvir

Source: Wikipedia, the free encyclopedia.
Ledipasvir/sofosbuvir
NS5B (RNA polymerase) inhibitor
Clinical data
Trade namesHarvoni, Hepcinat-LP, others
AHFS/Drugs.comMonograph
MedlinePlusa614051
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
JSmol)
  • CC(C)C(C(=O)N1CC2(CC2)CC1C3=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)C9C1CCC(C1)N9C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC.CC(C)OC(=O)C(C)NP(=O)(OCC1C(C(C(O1)N2C=CC(=O)NC2=O)(C)F)O)OC3=CC=CC=C3
  • InChI=1S/C49H54F2N8O6.C22H29FN3O9P/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;1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/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);5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t29-,30+,38-,39-,40-,41-;14-,16+,18+,20+,22+,36+/m00/s1
  • Key:YWRYBUCQWKGONV-CABNZSRHSA-N

Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat

fixed-dose combination of ledipasvir and sofosbuvir.[8] Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1.[9] Some evidence also supports use in HCV genotype 3 and 4.[9] It is taken daily by mouth for 8–24 weeks.[8]

It is generally well tolerated.

NS5B polymerase.[8]

Ledipasvir/sofosbuvir was approved for medical use in the United States, in the European Union, and in Canada in 2014.[8][11][7][12][13] It is on the World Health Organization's List of Essential Medicines.[14]

Medical uses

Cure rates are 94% to 99% in people infected with genotype 1 (46% of HCV cases).[15] 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).[9][6][16][15]

Resistance

NS5A mutations

Multiple mutations of HCV replicons are necessary to cause a significant effect in resistance due to multiple mechanisms of action.[17] In general, HCV genotype 1a is less resistant to mutation than genotype 1b.[18]

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.[18][19] 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.[6]

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).[6] 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.[6] Patients with multiple baseline NS5A polymorphisms tend to have higher relapse rates when using ledipasvir/sofosbuvir.[6] 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.[18][6]

NS5B mutations

A single amino acid substitution S282T contributes to viral resistance and decreases the activity of sofosbuvir in ledipasvir/sofosbuvir by approximately 2 to 18 fold.[18][20]

Cross resistance

No 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.[6][21]

Side effects

More 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.[6][5]

More severe reactions are connected with allergic reactions to the medications and cardiovascular problems. Harvoni side effects are considered relatively mild compared to older interferon-based treatment.[citation needed]

Ledipasvir/sofosbuvir could cause hepatitis B re-activation in people co-infected with hepatitis B and C viruses. The European Medicines Agency recommended screening all people for hepatitis B before starting ledipasvir/sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.[22]

Drug interactions

Ledipasvir/sofosbuvir is a substrate for the drug transporters

St. John's wort .[23]

Patients are also advised to stay away from

H2 receptor antagonists (H2RA) and proton-pump inhibitors (PPI) because they decrease the concentration of ledipasvir (its 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.[18][24]

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.[6][5]

Mechanisms of action

The most commonly associated mechanism associated with ledipasvir/sofosbuvir is the

NS5A, a viral polymerase important in proper viral assembly and interferes with proper liver metabolism.[25] Ledipasvir/sofosbuvir inhibits the proper viral assembly by re-positioning NS5A's sub-cellular localization.[18]

allosterically inhibited by ledipasvir/sofosbuvir.[26]

NS5A and NS5B inhibitors in combination have a synergistic effect.[27]

Pharmacokinetics

Sofosbuvir is absorbed fast in the plasma with a

fasting states.[29]

Ledipasvir has a maximum concentration at 4 to 4.5 hours after ingestion and is not affected by macronutrients.

protein bound and is predominantly eliminated fecally, with minimal metabolism in the liver.[6]

Elimination

The

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).[6][30]

Steady State (Cmax)
Substance ng/mL
Ledipasvir 323
Sofosbuvir 618
GS-331007 707

Note: The maximum concentration is 32% higher in healthy individuals than those infected with Hepatitis C.[6]

Mean Steady State AUC0-24 (Area Under the Curve During 24 hours)
Substance ng*hr/mL
Ledipasvir 7290
Sofosbuvir 1320
GS-33107 12,000

Note: The maximum concentration is 24% higher in healthy individuals than those infected with Hepatitis C.[6]

Blood detection

An 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.[31]

Society and culture

One manufacturer is Gilead Sciences.[8]

References

  1. ^ a b "Ledipasvir / sofosbuvir (Harvoni) Use During Pregnancy". Drugs.com. 28 October 2019. Retrieved 17 March 2020.
  2. ^ "AusPAR: Ledipasvir / Sofosbuvir". Therapeutic Goods Administration (TGA). 29 October 2015. Retrieved 29 August 2020.
  3. ^ "AusPAR: Sofosbuvir / Ledipasvir". Therapeutic Goods Administration (TGA). 16 November 2017. Retrieved 29 August 2020.
  4. ^ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  5. ^ a b c "Harvoni 90 mg/400 mg film-coated tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. December 2016. Archived from the original on 27 October 2016. Retrieved 4 February 2017.
  6. ^ a b c d e f g h i j k l m n o p "Harvoni- ledipasvir and sofosbuvir tablet, film coated Harvoni- ledipasvir and sofosbuvir tablet, film coated Harvoni- ledipasvir and sofosbuvir pellet". DailyMed. 16 March 2020. Retrieved 29 August 2020.
  7. ^ a b "Harvoni EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 August 2020.
  8. ^ a b c d e f g h "Ledipasvir and Sofosbuvir". The American Society of Health-System Pharmacists. Archived from the original on 25 December 2016. Retrieved 8 December 2016.
  9. ^
    S2CID 31943736
    .
  10. ISSN 0512-3054
    . WHO technical report series;994.
  11. ^ "Drug Approval Package:Harvoni (ledipasvir and sofosbuvir) Tablets NDA 205834". U.S. Food and Drug Administration (FDA). 3 November 2014. Retrieved 29 August 2020.
    "APPLICATION NUMBER: 205834Orig1s000" (PDF) (Summary Review). Center for Drug Evaluation and Research.
  12. ^ "Notice of Compliance (NOC) online query". 25 August 2010.
  13. ^ "Health Canada Issues Notice of Compliance for Gilead's Harvoni (Ledipasvir/Sofosbuvir), the First Once-Daily Single Tablet Regimen for the Treatment of Genotype 1 Chronic Hepatitis C" (Press release). Gilead Sciences, Inc. 16 October 2014. Retrieved 29 August 2020 – via Business Wire.
  14. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  15. ^
    PMID 25069599
    .
  16. PMID 25674658. Archived
    from the original on 5 November 2017.
  17. PMID 25384189
    .
  18. ^
    PMID 25859119
    .
  19. PMID 23896281
    .
  20. PMID 23199507
    .
  21. ^ "Harvoni Presribing Information" (PDF). Gilead Sciences. March 2020. Retrieved 2018-02-21.
  22. ^ "Direct-acting antivirals indicated for treatment of hepatitis C (interferon-free)". European Medicines Agency (EMA). 17 September 2018. Retrieved 4 February 2020.
  23. ^ "Drug Interactions Between Direct-Acting anti-HCV Antivirals Sofosbuvir and Ledipasvir and HIV Antiretrovirals". www.natap.org. Retrieved 2018-02-22.
  24. ^ "Impact of Food and Antacids on Levels of Ledipasvir and Sofosbuvir". www.natap.org. Retrieved 2018-02-22.
  25. PMID 11481452
    .
  26. PMID 30992888
    .
  27. PMID 23567084
    .
  28. ^ "Sofosbuvir". www.drugbank.ca. Retrieved 2018-03-23.
  29. PMID 26405313
    .
  30. ^ "Pharmacology: Basic Pharmacology, ANS, Endocrine". www.kumc.edu. Archived from the original on 2018-01-15. Retrieved 2018-03-23.
  31. PMID 27480956
    .

External links
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