Description

Simple

A medication used to treat hepatitis C virus infections.

Clinical

A direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

Overview

Daclatasvir is a direct-acting antiviral agent against Hepatitis C Virus (HCV) used for the treatment of chronic HCV genotype 1 and 3 infection. It is marketed under the name DAKLINZA and is contained in daily oral tablets as the hydrochloride salt form . Hepatitis C is 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 [8]. Daclatasvir was the first drug with demonstrated safety and therapeutic efficacy in treating HCV genotype 3 without the need for co-administration of interferon or [DB00811]. It exerts its antiviral action by preventing RNA replication and virion assembly via binding to NS5A, a nonstructural phosphoprotein encoded by HCV. Binding to the N-terminus of the D1 domain of NS5A prevents its interaction with host cell proteins and membranes required for virion replication complex assembly. Daclatasvir is shown to target both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status [Read more

Pharmacology

Indication

Indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic HCV genotype 1a/b or 3 infection. The dosing regimen of 60mg daclatasvir 60 mg with 400mg sofosbuvir once a day is recommended for both genontypes.

Resistance: Reduced susceptibility to daclatasvir was ass... Read more

Pharmacodynamic

Daclatasvir is a direct-acting antiviral agent that targets the NS5A and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of an NS5A protein in the replication complex [ Read more

Mechanism of action

NS5A is a viral nonstructural phospoprotein that is part of a functional replication complex in charge of viral RNA genome amplification on endoplasmic reticulum membranes. It has the ability to bind to HCV RNA. It is shown to have two distinct functions in HCV RNA replication based on phosphorylate... Read more

Absorption

Studies demonstrated that peak plasma concentrations typically occurred within 2 hours after administration of multiple oral doses ranging from 1 - 100 mg once daily. Steady state is reached after approximately 4 days of once-daily daclatasvir administration. The absolute bioavailability of the tabl... Read more

Protein binding

Daclatasvir is highly protein bound (99%).

Volume of distribution

The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously.

Clearance

In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h.

Half life

Following multiple dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours.

Route of elimination

Approximately 88% of total dose of daclatasvir is eliminated into bile and feces in which 53% remains as unchanged form, while 6.6% of the total dose is eliminated primarily unchanged in the urine.

Toxicity

The most common adverse effects experienced in patients undergoing daclatasvir and sofosbuvir therapy include headache, fatigue, nausea and diarrhea. Similar side effects are seen when ribavirin is added, in addition to rash, insomnia, anemia, dizziness and somnolence. There are postmarketing cases... Read more

Adverse Effects

Contraindications

  • Regions: US
  • With Categories Coadmin:
      • Name: Cytochrome P-450 CYP3A Inducers
      • Drugbank Id: DBCAT000492
      • Mesh Id: D065701
  • Regions: US
  • With Drugs Coadmin:
      • Name: Phenytoin
      • Drugbank Id: DB00252
  • Regions: US
  • With Drugs Coadmin:
      • Name: St. John's Wort
      • Drugbank Id: DB01323
  • Regions: US
  • With Drugs Coadmin:
      • Name: Carbamazepine
      • Drugbank Id: DB00564
  • Regions: US
  • With Drugs Coadmin:
      • Name: Rifampicin
      • Drugbank Id: DB01045

Food Interactions

    Information currently not available.

Interactions

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  • Paracetamol(acetaminophen)
  • Paxil(paroxetine)
  • Pamelor(nortriptyline)
  • Panadol(acetaminophen)
  • Patanol(olopatadine ophthalmic)
  • Pataday(olopatadine ophthalmic)
  • Parnate(tranylcypromine)
  • Pazeo(olopatadine ophthalmic)
Abatacept
The metabolism of Daclatasvir can be increased when combined with Abatacept.
Abemaciclib
Daclatasvir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Acalabrutinib
The metabolism of Daclatasvir can be decreased when combined with Acalabrutinib.
Acetyldigoxin
Daclatasvir may decrease the excretion rate of Acetyldigoxin which could result in a higher serum level.
Adalimumab
The metabolism of Daclatasvir can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine live
The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Daclatasvir.
Afatinib
The serum concentration of Afatinib can be increased when it is combined with Daclatasvir.
Afelimomab
The metabolism of Daclatasvir can be increased when combined with Afelimomab.
Alfentanil
The metabolism of Alfentanil can be decreased when combined with Daclatasvir.
Allopurinol
Daclatasvir may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Alpelisib
The serum concentration of Alpelisib can be increased when it is combined with Daclatasvir.
Alprazolam
The metabolism of Daclatasvir can be decreased when combined with Alprazolam.
Alvocidib
Daclatasvir may decrease the excretion rate of Alvocidib which could result in a higher serum level.
Ambrisentan
The serum concentration of Ambrisentan can be increased when it is combined with Daclatasvir.
Amiodarone
Daclatasvir may increase the bradycardic activities of Amiodarone.
Amitriptyline
The metabolism of Daclatasvir can be decreased when combined with Amitriptyline.
Amprenavir
The metabolism of Daclatasvir can be decreased when combined with Amprenavir.
Anakinra
The metabolism of Daclatasvir can be increased when combined with Anakinra.
Anthrax vaccine
The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Daclatasvir.
Apixaban
The serum concentration of Apixaban can be increased when it is combined with Daclatasvir.
9 References
  1. 1 . Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR 2nd, Colonno RJ, Gao M, Meanwell NA, Hamann LG: Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir. J Med Chem. 2014 Mar 13;57(5):2013-32. doi: 10.1021/jm401836p. Epub 2014 Feb 12.PubMed: 24521299
  2. 2 . Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, Layden TJ, Uprichard SL, Perelson AS: Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3991-6. doi: 10.1073/pnas.1203110110. Epub 2013 Feb 19.PubMed: 23431163
  3. 3 . Lee C: Daclatasvir: potential role in hepatitis C. Drug Des Devel Ther. 2013 Oct 16;7:1223-33. doi: 10.2147/DDDT.S40310. eCollection 2013.PubMed: 24204123
  4. 4 . Smith MA, Regal RE, Mohammad RA: Daclatasvir: A NS5A Replication Complex Inhibitor for Hepatitis C Infection. Ann Pharmacother. 2016 Jan;50(1):39-46. doi: 10.1177/1060028015610342. Epub 2015 Oct 20.PubMed: 26486762
  5. 5 . Berger C, Romero-Brey I, Radujkovic D, Terreux R, Zayas M, Paul D, Harak C, Hoppe S, Gao M, Penin F, Lohmann V, Bartenschlager R: Daclatasvir-like inhibitors of NS5A block early biogenesis of hepatitis C virus-induced membranous replication factories, independent of RNA replication. Gastroenterology. 2014 Nov;147(5):1094-105.e25. doi: 10.1053/j.gastro.2014.07.019. Epub 2014 Jul 18.PubMed: 25046163
  6. 6 . 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.PubMed: 25585348
  7. 7 . Li W, Zhao W, Liu X, Huang X, Lopez OD, Leet JE, Fancher RM, Nguyen V, Goodrich J, Easter J, Hong Y, Caceres-Cortes J, Chang SY, Ma L, Belema M, Hamann LG, Gao M, Zhu M, Shu YZ, Humphreys WG, Johnson BM: Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine delta-Oxidation and Rearrangement. Drug Metab Dispos. 2016 Jun;44(6):809-20. doi: 10.1124/dmd.115.068866. Epub 2016 Mar 30.PubMed: 27029743
  8. 8 . American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. Link
  9. 9 . American Liver Foundation: Advances in Medications to Treat Hepatitis C Link