Identification

Name
Sofosbuvir
Accession Number
DB08934
Type
Small Molecule
Groups
Approved
Description

Sofosbuvir (tradename Sovaldi) is a direct acting antiviral 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 [14]. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as sofosbuvir. As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) [Synthesis]. NS5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and for its high replicative rate and genetic diversity [4]. Sofosbuvir and other direct acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance [5]. 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 Sofosbuvir as first line therapy in combination with other antivirals for all six genotypes of Hepatitis C [14]. Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as Ledipasvir, Velpatasvir, Daclatasvir, Simeprevir, Elbasvir, Grazoprevir, Ribavirin, Peginterferon alfa-2a, or Peginterferon alfa-2b 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 sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue [FDA 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 [11].

Since 2014, sofosbuvir has been available as a fixed dose combination product with Ledipasvir (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 [FDA 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 [3]. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV [7].

Sofosbuvir is also available as a fixed dose combination product with Velpatasvir as the commercially available product Epclusa. First approved in June 2016, Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. Epclusa is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis [14]. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV [14, 6].

Notably, sofosbuvir has come under intense scrutiny since its release to market in 2013. With the price per pill set at $1000, a 12-week treatment can cost upwards of $84,000 per patient [12].

Structure
Thumb
Synonyms
  • S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)- (phenoxy)phosphorylamino)propanoate
External IDs
GI 7977 / GI-7977 / GI7977 / GS 331007 / GS 461203 / GS-331007 / GS-461203 / GS-7977 / GS331007 / GS461203 / GS7977 / PSI 7977 / PSI-7977 / PSI7977
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SovaldiTablet400 mgOralGilead Sciences2014-01-06Not applicableCanada
SovaldiTablet, film coated400 mg/1OralGilead Sciences2013-12-06Not applicableUs
SovaldiTablet, film coated400 mgOralGilead Sciences2014-01-16Not applicableEu
SovaldiTablet, film coated400 mgOralGilead Sciences2014-01-16Not applicableEu
International/Other Brands
Hepcinat (Natco Pharma Ltd.) / Hepcvir (Cipla Limited) / Resof (Hetero Drugs Ltd ) / SoviHep (Zydus Cadila)
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
EpclusaSofosbuvir (400 mg/1) + Velpatasvir (100 mg/1)Tablet, film coatedOralGilead Sciences2016-06-28Not applicableUs
EpclusaSofosbuvir (400 mg) + Velpatasvir (100 mg)TabletOralGilead Sciences2016-08-02Not applicableCanada
HarvoniSofosbuvir (400 mg) + Ledipasvir (90 mg)TabletOralGilead Sciences2014-10-16Not applicableCanada
HarvoniSofosbuvir (400 mg/1) + Ledipasvir (90 mg/1)Tablet, film coatedOralGilead Sciences2014-10-10Not applicableUs
VoseviSofosbuvir (400 mg/1) + Velpatasvir (100 mg/1) + Voxilaprevir (100 mg/1)Tablet, film coatedOralGilead Sciences2017-07-18Not applicableUs
VoseviSofosbuvir (400 mg) + Velpatasvir (100 mg) + Voxilaprevir (100 mg)TabletOralGilead Sciences2017-09-18Not applicableCanada
Categories
UNII
WJ6CA3ZU8B
CAS number
1190307-88-0
Weight
Average: 529.458
Monoisotopic: 529.162544687
Chemical Formula
C22H29FN3O9P
InChI Key
TTZHDVOVKQGIBA-IQWMDFIBSA-N
InChI
InChI=1S/C22H29FN3O9P/c1-13(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/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1
IUPAC Name
propan-2-yl (2S)-2-{[(S)-{[(2R,3R,4R,5R)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate
SMILES
CC(C)OC(=O)[[email protected]](C)N[[email protected]](=O)(OC[[email protected]]1O[[email protected]@H](N2C=CC(=O)NC2=O)[[email protected]](C)(F)[[email protected]@H]1O)OC1=CC=CC=C1

Pharmacology

Indication

Sofosbuvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include either ribavirin alone or ribavirin and peg-interferon alfa.

When used in combination with Ledipasvir as the combination product Harvoni, sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; in combination with Ribavirin for genotype 1 infection with decompensated cirrhosis; or in combination with Ribavirin for the treatment of genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis.

When used in combination with Velpatasvir as the combination product Epclusa, sofosbuvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis.

Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T [10].

Structured Indications
Pharmacodynamics

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent [FDA Label].

Mechanism of action

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator [Synthesis]. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material [13].

TargetActionsOrganism
ARNA-dependent RNA-polymerase
inhibitor
Hepatitis C virus
Absorption

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL [FDA Label].

Volume of distribution

The volume of distribution for sofosbuvir has yet to be determined [FDA Label].

Protein binding

Sofosbuvir is approximately 61-65% bound to human plasma proteins [FDA Label].

Metabolism

In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity [8, 9].

Route of elimination

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route [FDA Label].

Half life

Sofosbuvir has a terminal half life of 0.4 hours [FDA Label].

Clearance

The clearance of sofosbuvir has yet to be determined [FDA Label].

Toxicity

Sofosbuvir, as a single agent, has very mild toxicity. The most common adverse reactions are headache and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone [FDA Label].

Affected organisms
  • Hepatitis C Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AldosteroneThe serum concentration of Sofosbuvir can be decreased when it is combined with Aldosterone.Experimental, Investigational
AmiodaroneSofosbuvir may increase the bradycardic activities of Amiodarone.Approved, Investigational
AmprenavirThe serum concentration of Sofosbuvir can be decreased when it is combined with Amprenavir.Approved
CarbamazepineThe serum concentration of Sofosbuvir can be decreased when it is combined with Carbamazepine.Approved, Investigational
Cholic AcidThe serum concentration of Sofosbuvir can be decreased when it is combined with Cholic Acid.Approved
CimetidineThe serum concentration of Sofosbuvir can be decreased when it is combined with Cimetidine.Approved
ClotrimazoleThe serum concentration of Sofosbuvir can be decreased when it is combined with Clotrimazole.Approved, Vet Approved
CyclosporineThe serum concentration of Sofosbuvir can be decreased when it is combined with Cyclosporine.Approved, Investigational, Vet Approved
DaunorubicinThe serum concentration of Sofosbuvir can be decreased when it is combined with Daunorubicin.Approved
DexamethasoneThe serum concentration of Sofosbuvir can be decreased when it is combined with Dexamethasone.Approved, Investigational, Vet Approved
DigoxinThe serum concentration of Sofosbuvir can be decreased when it is combined with Digoxin.Approved
DoxorubicinThe serum concentration of Sofosbuvir can be decreased when it is combined with Doxorubicin.Approved, Investigational
EltrombopagThe serum concentration of Sofosbuvir can be increased when it is combined with Eltrombopag.Approved
EstriolThe serum concentration of Sofosbuvir can be decreased when it is combined with Estriol.Approved, Investigational, Vet Approved
EstroneThe serum concentration of Sofosbuvir can be decreased when it is combined with Estrone.Approved
IndinavirThe serum concentration of Sofosbuvir can be decreased when it is combined with Indinavir.Approved
LevothyroxineThe serum concentration of Sofosbuvir can be decreased when it is combined with Levothyroxine.Approved
LiothyronineThe serum concentration of Sofosbuvir can be decreased when it is combined with Liothyronine.Approved, Vet Approved
LiotrixThe serum concentration of Sofosbuvir can be decreased when it is combined with Liotrix.Approved
LumacaftorThe serum concentration of Sofosbuvir can be decreased when it is combined with Lumacaftor.Approved
MidazolamThe serum concentration of Sofosbuvir can be decreased when it is combined with Midazolam.Approved, Illicit
MifepristoneThe serum concentration of Sofosbuvir can be decreased when it is combined with Mifepristone.Approved, Investigational
MitoxantroneThe serum concentration of Sofosbuvir can be decreased when it is combined with Mitoxantrone.Approved, Investigational
ModafinilThe serum concentration of Sofosbuvir can be decreased when it is combined with Modafinil.Approved, Investigational
NefazodoneThe serum concentration of Sofosbuvir can be decreased when it is combined with Nefazodone.Approved, Withdrawn
NelfinavirThe serum concentration of Sofosbuvir can be decreased when it is combined with Nelfinavir.Approved
NifedipineThe serum concentration of Sofosbuvir can be decreased when it is combined with Nifedipine.Approved
NorethisteroneThe serum concentration of Sofosbuvir can be decreased when it is combined with Norethisterone.Approved
OxcarbazepineThe serum concentration of Sofosbuvir can be decreased when it is combined with Oxcarbazepine.Approved
PhenobarbitalThe serum concentration of Sofosbuvir can be decreased when it is combined with Phenobarbital.Approved
Platelet Activating FactorThe serum concentration of Sofosbuvir can be decreased when it is combined with Platelet Activating Factor.Experimental
ProgesteroneThe serum concentration of Sofosbuvir can be decreased when it is combined with Progesterone.Approved, Vet Approved
RanolazineThe serum concentration of Sofosbuvir can be increased when it is combined with Ranolazine.Approved, Investigational
ReserpineThe serum concentration of Sofosbuvir can be decreased when it is combined with Reserpine.Approved, Investigational
RifabutinThe serum concentration of Sofosbuvir can be decreased when it is combined with Rifabutin.Approved
RifampicinThe serum concentration of Sofosbuvir can be decreased when it is combined with Rifampicin.Approved
RifapentineThe serum concentration of Sofosbuvir can be decreased when it is combined with Rifapentine.Approved
RitonavirThe serum concentration of Sofosbuvir can be decreased when it is combined with Ritonavir.Approved, Investigational
RolapitantThe serum concentration of Sofosbuvir can be increased when it is combined with Rolapitant.Approved
SaquinavirThe serum concentration of Sofosbuvir can be decreased when it is combined with Saquinavir.Approved, Investigational
SirolimusThe serum concentration of Sofosbuvir can be decreased when it is combined with Sirolimus.Approved, Investigational
St. John's WortThe serum concentration of Sofosbuvir can be decreased when it is combined with St. John's Wort.Investigational, Nutraceutical
StreptozocinThe serum concentration of Sofosbuvir can be decreased when it is combined with Streptozocin.Approved
TacrolimusThe serum concentration of Sofosbuvir can be decreased when it is combined with Tacrolimus.Approved, Investigational
TamoxifenThe serum concentration of Sofosbuvir can be decreased when it is combined with Tamoxifen.Approved
TeriflunomideThe serum concentration of Sofosbuvir can be increased when it is combined with Teriflunomide.Approved
TesmilifeneThe serum concentration of Sofosbuvir can be decreased when it is combined with Tesmilifene.Investigational
TrazodoneThe serum concentration of Sofosbuvir can be decreased when it is combined with Trazodone.Approved, Investigational
TrimethoprimThe serum concentration of Sofosbuvir can be decreased when it is combined with Trimethoprim.Approved, Vet Approved
VerapamilThe serum concentration of Sofosbuvir can be decreased when it is combined with Verapamil.Approved
VinblastineThe serum concentration of Sofosbuvir can be decreased when it is combined with Vinblastine.Approved
VincristineThe serum concentration of Sofosbuvir can be decreased when it is combined with Vincristine.Approved, Investigational
Food Interactions
  • Sofosbuvir can be given with or without food.

References

Synthesis Reference

Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA: Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem. 2010 Oct 14;53(19):7202-18

General References
  1. Asselah T: Sofosbuvir for the treatment of hepatitis C virus. Expert Opin Pharmacother. 2014 Jan;15(1):121-30. doi: 10.1517/14656566.2014.857656. Epub 2013 Nov 30. [PubMed:24289735]
  2. Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J: Efficiency of incorporation and chain termination determines the inhibition potency of 2'-modified nucleotide analogs against hepatitis C virus polymerase. Antimicrob Agents Chemother. 2014 Jul;58(7):3636-45. doi: 10.1128/AAC.02666-14. Epub 2014 Apr 14. [PubMed:24733478]
  3. Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan C, Massetto B, Gaggar A, Ni L, Svarovskaia E, Brainard D, Subramanian GM, McHutchison JG, Puoti M, Rockstroh JK: Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet. 2015 Mar 21;385(9973):1098-106. doi: 10.1016/S0140-6736(14)62483-1. Epub 2015 Feb 4. [PubMed:25659285]
  4. Simmonds P: Genetic diversity and evolution of hepatitis C virus--15 years on. J Gen Virol. 2004 Nov;85(Pt 11):3173-88. [PubMed:15483230]
  5. 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. [PubMed:28497432]
  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. 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. [PubMed:26196665]
  8. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]
  9. Denning J, Cornpropst M, Flach SD, Berrey MM, Symonds WT: Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects. Antimicrob Agents Chemother. 2013 Mar;57(3):1201-8. doi: 10.1128/AAC.01262-12. Epub 2012 Dec 21. [PubMed:23262999]
  10. Xu S, Doehle B, Rajyaguru S, Han B, Barauskas O, Feng J, Perry J, Dvory-Sobol H, Svarovskaia ES, Miller MD, Mo H: In vitro selection of resistance to sofosbuvir in HCV replicons of genotype 1 to 6. Antivir Ther. 2017 Mar 1. doi: 10.3851/IMP3149. [PubMed:28248189]
  11. Dusheiko G: Side effects of alpha interferon in chronic hepatitis C. Hepatology. 1997 Sep;26(3 Suppl 1):112S-121S. [PubMed:9305675]
  12. Hill A, Simmons B, Gotham D, Fortunak J: Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C. J Virus Erad. 2016 Jan 1;2(1):28-31. [PubMed:27482432]
  13. Eltahla AA, Luciani F, White PA, Lloyd AR, Bull RA: Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance. Viruses. 2015 Sep 29;7(10):5206-24. doi: 10.3390/v7102868. [PubMed:26426038]
  14. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
External Links
KEGG Drug
D10366
PubChem Compound
45375808
PubChem Substance
175427164
ChemSpider
26286922
ChEBI
85083
ChEMBL
CHEMBL1259059
PharmGKB
PA166122593
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Sofosbuvir
ATC Codes
J05AX65 — Sofosbuvir and ledipasvirJ05AX15 — Sofosbuvir
AHFS Codes
  • 08:18.92 — Miscellaneous Antivirals
FDA label
Download (487 KB)
MSDS
Download (616 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedPreventionChronic Hepatitis C Virus (HCV) Infection1
0RecruitingTreatmentChronic Hepatitis C Infection / Lung Transplant Infection1
0RecruitingTreatmentChronic Hepatitis C Infection / Transplant, Kidney1
1CompletedNot AvailableHealthy Volunteers4
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentChronic Hepatitis C Infection1
1CompletedTreatmentHepatitis / Infection, Human Immunodeficiency Virus I1
1RecruitingTreatmentChronic Hepatitis C Infection / Pregnancy1
1, 2CompletedTreatmentChronic Hepatitis C Infection1
1, 2CompletedTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV)1
2Active Not RecruitingTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV) Infections1
2Active Not RecruitingTreatmentHepatitis C Virus Infection1
2Active Not RecruitingTreatmentHepatitis C, Chronic1
2CompletedNot AvailableHepatitis C, Chronic1
2CompletedTreatmentChronic Genotype 4 HCV / Chronic Genotype 5 HCV1
2CompletedTreatmentChronic HCV Infection3
2CompletedTreatmentChronic Hepatitis C Infection14
2CompletedTreatmentChronic Hepatitis C Infection / Hepatocellular,Carcinoma1
2CompletedTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV)1
2CompletedTreatmentChronic Hepatitis C Infection / Infection, Human Immunodeficiency Virus I1
2CompletedTreatmentChronic Hepatitis C Infection / Liver Cirrhosis / Portal Hypertension / With or Without Liver Decompensation1
2CompletedTreatmentChronic Hepatitis C Virus1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection3
2CompletedTreatmentChronic Hepatitis C Virus Infection1
2CompletedTreatmentHCV Infections3
2CompletedTreatmentHepatitis C Infection With HIV Co-Infection1
2CompletedTreatmentHepatitis C Virus (HCV)3
2CompletedTreatmentHepatitis C Virus Infection9
2CompletedTreatmentHepatitis C, Chronic4
2CompletedTreatmentHepatitits C1
2CompletedTreatmentPost Liver Transplant / Recurrent Chronic Hepatitis C Virus1
2CompletedTreatmentTreatment of Hepatitis C1
2Not Yet RecruitingTreatmentHepatitis Chronic Viral / Hepatitis E1
2Not Yet RecruitingTreatmentIndolent Lymphoma1
2Not Yet RecruitingTreatmentViral Hepatitis B1
2RecruitingTreatmentChronic Hepatitis C Infection1
2RecruitingTreatmentChronic Hepatitis C Infection / Porphyria Cutanea Tarda1
2RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection4
2RecruitingTreatmentHepatitis C Virus Infection4
2TerminatedTreatmentHepatitis C Infection1
2WithdrawnTreatmentChronic Hepatitis C Infection2
2, 3Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
2, 3RecruitingTreatmentChronic Hepatitis C Infection2
2, 3RecruitingTreatmentChronic Hepatitis C Infection / Cryoglobulinemia1
2, 3RecruitingTreatmentChronic Hepatitis C Infection / HBV Coinfection / Hepatitis B Reactivation1
3Active Not RecruitingNot AvailableChronic Hepatitis C Infection1
3Active Not RecruitingTreatmentChronic Hepatitis C Infection / Liver Cirrhosis1
3Active Not RecruitingTreatmentChronic Hepatitis C Virus / Hepatitis C Virus (HCV)1
3Active Not RecruitingTreatmentHepatitis C Virus Infection5
3Active Not RecruitingTreatmentHepatitis C, Chronic / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentChronic HCV Infection4
3CompletedTreatmentChronic Hepatitis C Infection12
3CompletedTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentChronic Hepatitis C Infection / Liver Cirrhosis1
3CompletedTreatmentChronic Hepatitis C Virus3
3CompletedTreatmentChronic Hepatitis C Virus (HCV Infection Genotype 1)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection4
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Genotype 3 Hepatitis C Virus / Hepatitis C Virus (HCV)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Genotype 4 Chronic Hepatitis C1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentHCV Infections / Infection, Human Immunodeficiency Virus I1
3CompletedTreatmentHepatitis C Infection1
3CompletedTreatmentHepatitis C Virus (HCV)1
3CompletedTreatmentHepatitis C Virus (HCV) / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentHepatitis C Virus Infection12
3Enrolling by InvitationTreatmentCirrhosis, Decompensated / Hepatitis C, Chronic1
3Enrolling by InvitationTreatmentHepatitis C Genotype 41
3Enrolling by InvitationTreatmentHepatitis C Virus Infection1
3Not Yet RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
3RecruitingTreatmentChronic Hepatitis C Infection1
3RecruitingTreatmentHepatitis C, Chronic / Hepatocellular,Carcinoma1
3TerminatedTreatmentHepatitis C Viral Infection1
4Active Not RecruitingTreatmentChronic Hepatitis C Infection3
4Active Not RecruitingTreatmentChronic Hepatitis C Infection / End-Stage Renal Disease (ESRD)1
4Active Not RecruitingTreatmentChronic Hepatitis C Infection / Liver Cirrhosis1
4CompletedTreatmentChronic Hepatitis C Infection3
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
4CompletedTreatmentHepatitis C Infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentHepatitis C Virus Infection1
4CompletedTreatmentHepatitis C Virus Infection, Response to Therapy of / Human Immunodeficiency Virus (HIV)1
4CompletedTreatmentHepatitis C, Chronic1
4CompletedTreatmentPT-NANBH1
4Enrolling by InvitationTreatmentHepatitis C, Chronic1
4Not Yet RecruitingHealth Services ResearchHepatitis C, Chronic / Opioid-use Disorder1
4Not Yet RecruitingPreventionChronic Hepatitis C Infection1
4Not Yet RecruitingPreventionChronic Hepatitis C Infection / End Stage Liver Diseases1
4Not Yet RecruitingTreatmentAntiviral Drug Adverse Reaction1
4Not Yet RecruitingTreatmentChronic Hepatitis C Infection / Hepatitis C, Chronic / Opiate Dependence1
4RecruitingTreatmentAwaiting Organ Transplant / Chronic Hepatitis C Infection1
4RecruitingTreatmentChronic Hepatitis C Infection4
4RecruitingTreatmentChronic Hepatitis C Infection / HCV1
4RecruitingTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV)1
4RecruitingTreatmentChronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV) / Liver Cirrhosis1
4RecruitingTreatmentChronic Hepatitis C Infection / Thalassaemic disorders1
4RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection3
4RecruitingTreatmentChronic Renal Failure (CRF) / Hepatitis C, Chronic1
4RecruitingTreatmentGenotype 1 Hepatitis C Virus1
4RecruitingTreatmentHCV Coinfection / Human Immunodeficiency Virus (HIV) / Liver Diseases1
4RecruitingTreatmentHeart Failure, Unspecified / Hepatitis C, Chronic / Lung Diseases, Interstitial / Pulmonary Disease, Chronic Obstructive1
4RecruitingTreatmentHematopoietic Stem Cell Transplantation (HSCT)1
4RecruitingTreatmentHepatitis C, Chronic1
4RecruitingTreatmentHepatitis C, Chronic / Lung Transplant1
4TerminatedTreatmentLiver Diseases1
4WithdrawnTreatmentHCV1
4WithdrawnTreatmentHepatitis C, Chronic / HIV CDC Category A11
4WithdrawnTreatmentPT-NANBH1
Not AvailableActive Not RecruitingNot AvailableChronic Hepatitis C Infection1
Not AvailableActive Not RecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection / Liver Cirrhosis1
Not AvailableActive Not RecruitingNot AvailableHepatitis C Virus Infection1
Not AvailableApproved for MarketingNot AvailablePost-transplant Hepatitis C1
Not AvailableCompletedNot AvailableChronic Hepatitis C (Disorder)1
Not AvailableCompletedNot AvailableChronic Hepatitis C Infection2
Not AvailableEnrolling by InvitationNot AvailableChronic Hepatitis C Infection1
Not AvailableEnrolling by InvitationNot AvailableHepatitis C Virus Infection2
Not AvailableNo Longer AvailableNot AvailableChronic Hepatitis C Virus (HCV) Infection2
Not AvailableNot Yet RecruitingNot AvailableChronic Hepatitis C Infection3
Not AvailableNot Yet RecruitingTreatmentCardiac Transplant / Chronic Hepatitis C Infection1
Not AvailableNot Yet RecruitingTreatmentChronic Hepatitis C Infection1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Infection2
Not AvailableRecruitingNot AvailableHCV Infections1
Not AvailableRecruitingNot AvailableHepatitis C Virus (HCV)3
Not AvailableRecruitingNot AvailableHepatitis C, Chronic / Human Immunodeficiency Virus (HIV)1
Not AvailableRecruitingBasic ScienceInsulin Resistance1
Not AvailableRecruitingScreeningHepatitis C, Chronic1
Not AvailableRecruitingTreatmentChronic Hepatitis C Infection / Chronic Kidney Disease (CKD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
TabletOral400 mg
Tablet, film coatedOral400 mg/1
Tablet, film coatedOral400 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8841278No2010-05-122030-05-12Us
US7964580No2009-03-262029-03-26Us
US8334270No2008-03-212028-03-21Us
US8822430No2010-05-122030-05-12Us
US8633309No2009-03-262029-03-26Us
US8273341No2010-05-122030-05-12Us
US8618076No2010-12-112030-12-11Us
US8735372No2008-03-212028-03-21Us
US8580765No2008-03-212028-03-21Us
US8889159No2009-03-262029-03-26Us
US9085573No2008-03-212028-03-21Us
US9284342No2010-09-132030-09-13Us
US8088368No2010-05-122030-05-12Us
US9393256No2012-09-142032-09-14Us
US9511056No2010-05-122030-05-12Us
US9549941No2009-03-262029-03-26Us
US8940718No2012-11-162032-11-16Us
US8575135No2012-11-162032-11-16Us
US8921341No2012-11-162032-11-16Us
US9585906No2008-03-212028-03-21Us
US9296782No2014-07-172034-07-17Us
US9757406No2014-01-302034-01-30Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.62FDA Label
pKa9.3FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.824 mg/mLALOGPS
logP1.63ALOGPS
logP1.28ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.7ChemAxon
pKa (Strongest Basic)-3.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area152.73 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity121.59 m3·mol-1ChemAxon
Polarizability49.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2'-deoxyribonucleosides
Direct Parent
Pyrimidine 2'-deoxyribonucleosides
Alternative Parents
Alpha amino acid esters / Alanine and derivatives / Phosphoric diester monoamides / Phenoxy compounds / Pyrimidones / Hydropyrimidines / Organic phosphoramides / Vinylogous amides / Tetrahydrofurans / Heteroaromatic compounds
show 15 more
Substituents
Pyrimidine 2'-deoxyribonucleoside / Alpha-amino acid ester / Alanine or derivatives / Alpha-amino acid or derivatives / Phenoxy compound / Phosphoric diester monoamide / Pyrimidone / Monocyclic benzene moiety / Benzenoid / Hydropyrimidine
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, ring assembly, L-alanyl ester, phosphoramidate ester, nucleotide conjugate (CHEBI:85083)

Targets

Kind
Protein
Organism
Hepatitis C virus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Rna-directed rna polymerase activity
Specific Function
Not Available
Gene Name
NS5b
Uniprot ID
O39930
Uniprot Name
RNA-dependent RNA-polymerase
Molecular Weight
65753.05 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]

Enzymes

Kind
Protein
Organism
Not Available
Pharmacological action
Unknown
Actions
Substrate
General Function
Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.
Specific Function
Carboxypeptidase activity
Gene Name
CTSA
Uniprot ID
P10619
Uniprot Name
Lysosomal protective protein
Molecular Weight
54465.655 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein kinase c binding
Specific Function
Hydrolyzes purine nucleotide phosphoramidates with a single phosphate group, including adenosine 5'monophosphoramidate (AMP-NH2), adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosin...
Gene Name
HINT1
Uniprot ID
P49773
Uniprot Name
Histidine triad nucleotide-binding protein 1
Molecular Weight
13801.815 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Uridylate kinase activity
Specific Function
Catalyzes the phosphorylation of pyrimidine nucleoside monophosphates at the expense of ATP. Plays an important role in de novo pyrimidine nucleotide biosynthesis. Has preference for UMP and CMP as...
Gene Name
CMPK1
Uniprot ID
P30085
Uniprot Name
UMP-CMP kinase
Molecular Weight
22222.175 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Ribosomal small subunit binding
Specific Function
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-sit...
Gene Name
NME1
Uniprot ID
P15531
Uniprot Name
Nucleoside diphosphate kinase A
Molecular Weight
17148.635 Da
References
  1. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26. [PubMed:20801890]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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
  1. Tischer S, Fontana RJ: Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting. J Hepatol. 2014 Apr;60(4):872-84. doi: 10.1016/j.jhep.2013.11.013. Epub 2013 Nov 23. [PubMed:24280292]
  2. Burgess S, Partovi N, Yoshida EM, Erb SR, Azalgara VM, Hussaini T: Drug Interactions With Direct-Acting Antivirals for Hepatitis C: Implications for HIV and Transplant Patients. Ann Pharmacother. 2015 Jun;49(6):674-87. doi: 10.1177/1060028015576180. Epub 2015 Mar 13. [PubMed:25770114]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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 on January 01, 2014 21:48 / Updated on November 19, 2017 20:33