Ledipasvir/sofosbuvir

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Ledipasvir/sofosbuvir
Ledipasvir and sofosbuvir.svg
Combination of
Ledipasvir NS5A inhibitor
Sofosbuvir NS5B (RNA polymerase) inhibitor
Clinical data
Trade names Harvoni, Hepcinat-LP, others
AHFS/Drugs.com Monograph
MedlinePlus a614051
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
PubChem CID
KEGG
Chemical and physical data
Formula C71H83F3N11O15P
Molar mass 1418.476 g·mol−1
3D model (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 hepatitis C. [8] It is a 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]

Contents

It is generally well tolerated. [10] Common side effects include muscle pains, headache, nausea, rash, and cough. [8] It is unclear if use in pregnancy is safe for the baby. [8] Ledipasvir works by decreasing the activity of NS5A and sofosbuvir works by decreasing the activity of 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 P-Glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [18] Intestinal absorption of these drug transporter substrates may be decreased by inducers such as rifampin and 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 hyperphosphorylation of 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]

NS5B, a viral polymerase that can initiate RNA synthesis de novo, is also 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 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. [28] [18] 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. [6] Sofosbuvir does not appear to be affected by different levels of macronutrients when compared with fasting states. [29]

Ledipasvir has a maximum concentration at 4 to 4.5 hours after ingestion and is not affected by macronutrients. [18] [6] It is more than 98% 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)
Substanceng/mL
Ledipasvir323
Sofosbuvir618
GS-331007707

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)
Substanceng*hr/mL
Ledipasvir7290
Sofosbuvir1320
GS-3310712,000

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]

Related Research Articles

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

<span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

<span class="mw-page-title-main">Daclatasvir</span> Chemical compound

Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depending on the virus type and whether the person has cirrhosis. It is taken by mouth.

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

<span class="mw-page-title-main">Ledipasvir</span> Hepatitis C drug

Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. 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. 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.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5B</span>

Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis C virus (HCV). It is an RNA-dependent RNA polymerase, having the key function of replicating HCV's viral RNA by using the viral positive RNA strand as a template to catalyze the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication. Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK. The structure can be represented by a right hand shape with fingers, palm, and thumb. The encircled active site, unique to NS5B, is contained within the palm structure of the protein. Recent studies on NS5B protein genotype 1b strain J4's (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. De-novo adds necessary primers for initiation of RNA replication.

<span class="mw-page-title-main">Ombitasvir</span> Chemical compound

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.

Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

<span class="mw-page-title-main">Velpatasvir</span> Chemical compound

Velpatasvir is an NS5A inhibitor which is used together with sofosbuvir in the treatment of hepatitis C infection of all six major genotypes.

<span class="mw-page-title-main">Sofosbuvir/daclatasvir</span> Combination drug

Daclatasvir/sofosbuvir is a two-drug combination for the treatment of hepatitis C. It is given as a single daily pill containing daclatasvir, a viral NS5A inhibitor, and sofosbuvir, a nucleotide inhibitor of the viral RNA polymerase NS5B.

<span class="mw-page-title-main">Discovery and development of NS5A inhibitors</span>

Nonstructural protein 5A (NS5A) inhibitors are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle combined with advances in drug discovery technology. However, their mechanism of action is complex and not fully understood. NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014. Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent. Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.

<span class="mw-page-title-main">Glecaprevir</span> Chemical compound

Glecaprevir (INN,) is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that was identified jointly by AbbVie and Enanta Pharmaceuticals. It is being developed as a treatment of chronic hepatitis C infection in co-formulation with an HCV NS5A inhibitor pibrentasvir. Together they demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro.

Sofosbuvir/velpatasvir, sold under the brand name Epclusa among others, is a fixed-dose combination medication for the treatment of hepatitis C in adults. It combines sofosbuvir and velpatasvir. It is more than 90% effective for hepatitis C genotypes one through six. It also works for hepatitis C in those who also have cirrhosis or HIV/AIDS. It is taken by mouth.

Glecaprevir/pibrentasvir (G/P), sold under the brand names Mavyret and Maviret, is a fixed-dose combination medication used to treat hepatitis C. It contains glecaprevir and pibrentasvir. It works against all six types of hepatitis C. At twelve weeks following treatment between 81% and 100% of people have no evidence of hepatitis C. It is taken once a day by mouth with food.

<span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

<span class="mw-page-title-main">Interferon Lambda 4</span> Protein-coding gene in the species Homo sapiens

Interferon lambda 4 is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.

<span class="mw-page-title-main">Uprifosbuvir</span> Chemical compound

Uprifosbuvir (MK-3682) is an antiviral drug developed for the treatment of hepatitis C. It is a nucleotide analogue which acts as an NS5B RNA polymerase inhibitor. As of 2019 it was in Phase III human clinical trials.

References

  1. ↑ "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. 1 2 3 "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. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "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. 1 2 "Harvoni EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 August 2020.
  8. 1 2 3 4 5 6 7 8 "Ledipasvir and Sofosbuvir". The American Society of Health-System Pharmacists. Archived from the original on 25 December 2016. Retrieved 8 December 2016.
  9. 1 2 3 Keating GM (April 2015). "Ledipasvir/Sofosbuvir: a review of its use in chronic hepatitis C". Drugs. 75 (6): 675–685. doi:10.1007/s40265-015-0381-2. PMID   25837989. S2CID   31943736.
  10. ↑ World Health Organization (2015). 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). Geneva: World Health Organization. pp. 69–70. hdl: 10665/189763 . ISBN   9789241209946. 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. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  15. 1 2 Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, Barnes E (January 2015). "Global distribution and prevalence of hepatitis C virus genotypes". Hepatology. 61 (1): 77–87. doi:10.1002/hep.27259. PMC   4303918 . PMID   25069599.
  16. ↑ "Holkira (Ombitasvir/Paritaprevir/ Ritonavir with Dasabuvir) and Harvoni (Ledipasvir/Sofosbuvir) for Chronic Hepatitis C: A Review of the Clinical Evidence". Rapid Response Service. Canadian Agency for Drugs and Technologies in Health. 16 January 2015. PMID   25674658. Archived from the original on 5 November 2017.
  17. ↑ Issur M, Götte M (November 2014). "Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding". Viruses. 6 (11): 4227–4241. doi: 10.3390/v6114227 . PMC   4246218 . PMID   25384189.
  18. 1 2 3 4 5 6 7 8 9 Gritsenko D, Hughes G (April 2015). "Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection". P & T. 40 (4): 256–276. PMC   4378517 . PMID   25859119.
  19. ↑ Gao M (October 2013). "Antiviral activity and resistance of HCV NS5A replication complex inhibitors". Current Opinion in Virology. 3 (5): 514–520. doi:10.1016/j.coviro.2013.06.014. PMID   23896281.
  20. ↑ Vermehren J, Sarrazin C (August 2012). "The role of resistance in HCV treatment". Best Practice & Research. Clinical Gastroenterology. 26 (4): 487–503. doi:10.1016/j.bpg.2012.09.011. 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. ↑ Gong G, Waris G, Tanveer R, Siddiqui A (August 2001). "Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9599–9604. Bibcode:2001PNAS...98.9599G. doi: 10.1073/pnas.171311298 . PMC   55498 . PMID   11481452.
  26. ↑ Lin MV, Chung R (March 2014). "Recent FDA approval of sofosbuvir and simeprevir. Implications for current HCV treatment". Clinical Liver Disease. 3 (3): 65–68. doi:10.1002/cld.332. PMC   6448702 . PMID   30992888.
  27. ↑ Pawlotsky JM (August 2013). "NS5A inhibitors in the treatment of hepatitis C". Journal of Hepatology. 59 (2): 375–382. doi: 10.1016/j.jhep.2013.03.030 . PMID   23567084.
  28. ↑ "Sofosbuvir". www.drugbank.ca. Retrieved 2018-03-23.
  29. ↑ Cada DJ, Baker DE, Bindler RJ (March 2015). "Ledipasvir/Sofosbuvir". Hospital Pharmacy. 50 (3): 224–234. doi:10.1310/hpj5003-224. PMC   4567193 . PMID   26405313.
  30. ↑ "Pharmacology: Basic Pharmacology, ANS, Endocrine". www.kumc.edu. Archived from the original on 2018-01-15. Retrieved 2018-03-23.
  31. ↑ Elkady EF, Aboelwafa AA (September 2016). "A Rapid and Optimized LC-MS/MS Method for the Simultaneous Extraction and Determination of Sofosbuvir and Ledipasvir in Human Plasma". Journal of AOAC International. 99 (5): 1252–1259. doi:10.5740/jaoacint.16-0021. PMID   27480956.
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