Identification

Name
Daclatasvir
Accession Number
DB09102
Type
Small Molecule
Groups
Approved, Investigational
Description

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 Ribavirin. 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 [3]. The most common critical NS5A amino acid substitutions that led to reduced susceptibility to daclatasvir therapy occured at position Q30 (Q30H/K/R) and M28 in genotype 1a patients and Y93H in genotype 3 patients.

According to 2017 American Association for the Study of Liver Diseases (AASLD), 60mg of daclatasvir is recommended with 400mg Sofosbuvir for genotype 1a/b patients with or without cirrhosis as second-line therapy. The same dosing regimen can be used as first-line therapy in patients with genotype 3 without cirrhosis and second-line therapy in genotype 3 patients with compensated cirrhosis. Combination therapies that include daclatasir can be used for challenging-to-treat patients who have HIV-1 coinfection, advanced cirrhosis, or post-liver transplant recurrence of HCV [9]. The therapy is intended to cure or achieve a sustained virologic response (SVR12), 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].

Daclatasvir was FDA-approved in July 2015 for use with Sofosbuvir (Sovaldi) with or without Ribavirin to treat HCV genotype 1 and 3 infections. The SVR12 in HCV genotype 1a-infected treatment-naïve subjects without and with cirrhosis undergoing daclatasvir and Sofosbuvir therapy were 88% and 99%, respectively [Label]. The same dosing regimen in treatment-naïve patients with HCV genotype 3 infection with or without cirrhosis achieved SVR12 rates of 71% and 98%, respectively [Label].

Structure
Thumb
Synonyms
  • BMS-790052
External IDs
BMS 790052 / BMS 790052-05 / BMS-790052-05 / EBP 883 / EBP-883
Product Ingredients
IngredientUNIICASInChI Key
Daclatasvir dihydrochloride50ZO25C11D1009119-65-6BVZLLUDATICXCI-JMSCDMLISA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DaklinzaTablet30 mgOralBristol Myers Squibb2015-09-08Not applicableCanada
DaklinzaTablet30 mg/1OralE.R. Squibb & Sons, L.L.C.2015-07-27Not applicableUs
DaklinzaTablet90 mg/1OralE.R. Squibb & Sons, L.L.C.2016-05-18Not applicableUs
DaklinzaTablet60 mgOralBristol Myers Squibb2015-09-08Not applicableCanada
DaklinzaTablet60 mg/1OralE.R. Squibb & Sons, L.L.C.2015-07-27Not applicableUs
Categories
UNII
LI2427F9CI
CAS number
1009119-64-5
Weight
Average: 738.89
Monoisotopic: 738.385331362
Chemical Formula
C40H50N8O6
InChI Key
FKRSSPOQAMALKA-CUPIEXAXSA-N
InChI
InChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1
IUPAC Name
methyl N-[(2S)-1-[(2S)-2-[5-(4'-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
SMILES
COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC=C(N1)C1=CC=C(C=C1)C1=CC=C(C=C1)C1=CN=C(N1)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC)C(C)C

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 associated with the polymorphisms at NS5A amino acid positions M28, Q30, L31, and Y93 in genotypes 1a, 1b, and 3a patients. NS5A Resistance Testing is recommended for HCV genotype 1a-infected patients with cirrhosis prior to the initiaition of the treatment, as the risk of resistance development is higher in genotype 1a patients.

Associated Conditions
Pharmacodynamics

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 [3]. It is shown to cause downregulation of the hyperphosphorylation of NS5A. It does not appear to prolong the QT interval even when given at 3 times the maximum recommended dose.

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 phosphorylated states. Maintaining the HCV replication complex is mediated by the cis-acting function of basally phosphorylated NS5A and the trans-acting function of hyperphosphorylated NS5A modulates HCV assembly and infectious particle formation [3]. Daclatasvir is shown to disrupt hyperphosphorylated NS5A proteins thus interfere with the function of new HCV replication complexes. It is also reported that daclatasvir also blocks both intracellular viral RNA synthesis and virion assembly/secretion in vivo [2].

TargetActionsOrganism
UNonstructural Protein 5A (NS5A)
inhibitor
Hepatitis C Virus (HCV)
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 tablet formulation is 67%.

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.

Protein binding

Daclatasvir is highly protein bound (99%).

Metabolism

Daclastavir is a substrate of CYP3A enzymes where its metabolism is predominantly mediated by CYP3A4 isoform. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom [7]. High proportion of the drug in the plasma (greater than 97%) is in the unchanged form.

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.

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.

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.

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 that link serious symptomatic bradycardia with Daklinza when used in conjunction with sofosbuvir and amiodarone. Coadministration of these three drugs is not recommended unless there are no other alternatives.

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

Interactions

Drug Interactions
DrugInteractionDrug group
Acetyl sulfisoxazoleThe metabolism of Daclatasvir can be decreased when combined with Acetyl sulfisoxazole.Approved, Vet Approved
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Daclatasvir.Approved
AmiodaroneDaclatasvir may increase the bradycardic activities of Amiodarone.Approved, Investigational
ApalutamideThe serum concentration of Daclatasvir can be decreased when it is combined with Apalutamide.Approved, Investigational
AprepitantThe serum concentration of Daclatasvir can be increased when it is combined with Aprepitant.Approved, Investigational
AtazanavirThe serum concentration of Daclatasvir can be increased when it is combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Daclatasvir can be decreased when combined with Atomoxetine.Approved
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Daclatasvir.Approved
BoceprevirThe serum concentration of Daclatasvir can be increased when it is combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Daclatasvir can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Daclatasvir can be decreased when it is combined with Bosentan.Approved, Investigational
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Daclatasvir.Approved
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Daclatasvir.Approved, Investigational
CarbamazepineThe serum concentration of Daclatasvir can be decreased when it is combined with Carbamazepine.Approved, Investigational
CeritinibThe serum concentration of Daclatasvir can be increased when it is combined with Ceritinib.Approved
CerivastatinThe serum concentration of Cerivastatin can be increased when it is combined with Daclatasvir.Approved, Withdrawn
CimetidineThe serum concentration of Cimetidine can be increased when it is combined with Daclatasvir.Approved, Investigational
CiprofloxacinThe serum concentration of Ciprofloxacin can be increased when it is combined with Daclatasvir.Approved, Investigational
ClarithromycinThe serum concentration of Daclatasvir can be increased when it is combined with Clarithromycin.Approved
ClotrimazoleThe serum concentration of Daclatasvir can be increased when it is combined with Clotrimazole.Approved, Vet Approved
CobicistatThe serum concentration of Daclatasvir can be increased when it is combined with Cobicistat.Approved
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Daclatasvir.Approved
ConivaptanThe serum concentration of Conivaptan can be increased when it is combined with Daclatasvir.Approved, Investigational
CrizotinibThe metabolism of Daclatasvir can be decreased when combined with Crizotinib.Approved
CurcuminThe serum concentration of Daclatasvir can be increased when it is combined with Curcumin.Approved, Investigational
CyclosporineThe serum concentration of Cyclosporine can be increased when it is combined with Daclatasvir.Approved, Investigational, Vet Approved
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Daclatasvir.Approved
DabrafenibThe serum concentration of Daclatasvir can be decreased when it is combined with Dabrafenib.Approved, Investigational
DapagliflozinThe serum concentration of Dapagliflozin can be increased when it is combined with Daclatasvir.Approved
DarunavirThe serum concentration of Daclatasvir can be increased when it is combined with Darunavir.Approved
DasatinibThe serum concentration of Daclatasvir can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Daclatasvir can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Daclatasvir can be decreased when combined with Delavirdine.Approved
DexamethasoneThe serum concentration of Daclatasvir can be decreased when it is combined with Dexamethasone.Approved, Investigational, Vet Approved
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Daclatasvir.Approved
DihydroergotamineThe metabolism of Daclatasvir can be decreased when combined with Dihydroergotamine.Approved, Investigational
DiltiazemThe serum concentration of Daclatasvir can be increased when it is combined with Diltiazem.Approved, Investigational
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Daclatasvir.Approved, Investigational
DoxycyclineThe metabolism of Daclatasvir can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Daclatasvir can be decreased when combined with Dronedarone.Approved
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Daclatasvir.Approved
EnzalutamideThe serum concentration of Daclatasvir can be decreased when it is combined with Enzalutamide.Approved
ErythromycinThe metabolism of Daclatasvir can be decreased when combined with Erythromycin.Approved, Investigational, Vet Approved
EstradiolThe serum concentration of Estradiol can be increased when it is combined with Daclatasvir.Approved, Investigational, Vet Approved
Ethinyl EstradiolThe serum concentration of Ethinyl Estradiol can be increased when it is combined with Daclatasvir.Approved
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Daclatasvir.Approved
FluconazoleThe metabolism of Daclatasvir can be decreased when combined with Fluconazole.Approved, Investigational
Fluticasone propionateThe serum concentration of Fluticasone propionate can be increased when it is combined with Daclatasvir.Approved
FluvastatinThe excretion of Fluvastatin can be decreased when combined with Daclatasvir.Approved
FluvoxamineThe metabolism of Daclatasvir can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Daclatasvir can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Daclatasvir can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe serum concentration of Daclatasvir can be decreased when it is combined with Fosphenytoin.Approved, Investigational
Fusidic AcidThe serum concentration of Daclatasvir can be increased when it is combined with Fusidic Acid.Approved, Investigational
GlyburideThe serum concentration of Glyburide can be increased when it is combined with Daclatasvir.Approved
HydrocortisoneThe serum concentration of Hydrocortisone can be increased when it is combined with Daclatasvir.Approved, Vet Approved
IdelalisibThe serum concentration of Daclatasvir can be increased when it is combined with Idelalisib.Approved
ImatinibThe metabolism of Daclatasvir can be decreased when combined with Imatinib.Approved
IndinavirThe serum concentration of Daclatasvir can be increased when it is combined with Indinavir.Approved
IrinotecanThe serum concentration of Irinotecan can be increased when it is combined with Daclatasvir.Approved, Investigational
IsavuconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Isavuconazole.Approved, Investigational
IsavuconazoniumThe metabolism of Daclatasvir can be decreased when combined with Isavuconazonium.Approved, Investigational
ItraconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Daclatasvir can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Ketoconazole.Approved, Investigational
LamivudineThe serum concentration of Lamivudine can be increased when it is combined with Daclatasvir.Approved, Investigational
LamotrigineThe serum concentration of Lamotrigine can be increased when it is combined with Daclatasvir.Approved, Investigational
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Daclatasvir.Approved
LevetiracetamThe serum concentration of Levetiracetam can be increased when it is combined with Daclatasvir.Approved, Investigational
LoperamideThe serum concentration of Loperamide can be increased when it is combined with Daclatasvir.Approved
LopinavirThe serum concentration of Daclatasvir can be increased when it is combined with Lopinavir.Approved
LorpiprazoleThe serum concentration of Daclatasvir can be increased when it is combined with Lorpiprazole.Approved
LosartanThe serum concentration of Losartan can be increased when it is combined with Daclatasvir.Approved
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Daclatasvir.Approved, Investigational
LuliconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Luliconazole.Approved
LumacaftorThe serum concentration of Daclatasvir can be decreased when it is combined with Lumacaftor.Approved
MethylprednisoloneThe serum concentration of Methylprednisolone can be increased when it is combined with Daclatasvir.Approved, Vet Approved
MevastatinThe serum concentration of Mevastatin can be increased when it is combined with Daclatasvir.Experimental
MibefradilThe serum concentration of Daclatasvir can be increased when it is combined with Mibefradil.Investigational, Withdrawn
MiconazoleThe metabolism of Daclatasvir can be decreased when combined with Miconazole.Approved, Investigational, Vet Approved
MifepristoneThe serum concentration of Daclatasvir can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Daclatasvir can be decreased when it is combined with Mitotane.Approved
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Daclatasvir.Approved
NefazodoneThe serum concentration of Daclatasvir can be increased when it is combined with Nefazodone.Approved, Withdrawn
NelfinavirThe serum concentration of Daclatasvir can be increased when it is combined with Nelfinavir.Approved
NetupitantThe serum concentration of Daclatasvir can be increased when it is combined with Netupitant.Approved, Investigational
NevirapineThe serum concentration of Daclatasvir can be decreased when it is combined with Nevirapine.Approved
NicardipineThe serum concentration of Nicardipine can be increased when it is combined with Daclatasvir.Approved, Investigational
NifedipineThe serum concentration of Nifedipine can be increased when it is combined with Daclatasvir.Approved
NilotinibThe metabolism of Daclatasvir can be decreased when combined with Nilotinib.Approved, Investigational
OlaparibThe metabolism of Daclatasvir can be decreased when combined with Olaparib.Approved
OmeprazoleThe serum concentration of Omeprazole can be increased when it is combined with Daclatasvir.Approved, Investigational, Vet Approved
OndansetronThe serum concentration of Ondansetron can be increased when it is combined with Daclatasvir.Approved
OsimertinibThe serum concentration of Daclatasvir can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Daclatasvir can be increased when it is combined with Palbociclib.Approved, Investigational
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Daclatasvir.Approved
PentobarbitalThe serum concentration of Daclatasvir can be decreased when it is combined with Pentobarbital.Approved, Investigational, Vet Approved
PhenobarbitalThe serum concentration of Daclatasvir can be decreased when it is combined with Phenobarbital.Approved, Investigational
PhenytoinThe serum concentration of Daclatasvir can be decreased when it is combined with Phenytoin.Approved, Vet Approved
PitavastatinThe serum concentration of Pitavastatin can be increased when it is combined with Daclatasvir.Approved
PitolisantThe serum concentration of Daclatasvir can be decreased when it is combined with Pitolisant.Approved, Investigational
PosaconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Posaconazole.Approved, Investigational, Vet Approved
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Daclatasvir.Approved
PrednisoloneThe serum concentration of Prednisolone can be increased when it is combined with Daclatasvir.Approved, Vet Approved
PrimidoneThe serum concentration of Daclatasvir can be decreased when it is combined with Primidone.Approved, Vet Approved
PropranololThe serum concentration of Propranolol can be increased when it is combined with Daclatasvir.Approved, Investigational
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Daclatasvir.Approved
QuetiapineThe serum concentration of Quetiapine can be increased when it is combined with Daclatasvir.Approved
RanitidineThe serum concentration of Ranitidine can be increased when it is combined with Daclatasvir.Approved
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Daclatasvir.Approved, Investigational
RifabutinThe serum concentration of Daclatasvir can be decreased when it is combined with Rifabutin.Approved, Investigational
RifampicinThe serum concentration of Daclatasvir can be decreased when it is combined with Rifampicin.Approved
RifapentineThe serum concentration of Daclatasvir can be decreased when it is combined with Rifapentine.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Daclatasvir.Approved, Investigational
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Daclatasvir.Approved
RucaparibThe metabolism of Daclatasvir can be decreased when combined with Rucaparib.Approved, Investigational
SaquinavirThe serum concentration of Daclatasvir can be increased when it is combined with Saquinavir.Approved, Investigational
SarilumabThe therapeutic efficacy of Daclatasvir can be decreased when used in combination with Sarilumab.Approved, Investigational
SildenafilThe metabolism of Daclatasvir can be decreased when combined with Sildenafil.Approved, Investigational
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Daclatasvir.Approved
SiltuximabThe serum concentration of Daclatasvir can be decreased when it is combined with Siltuximab.Approved, Investigational
SimeprevirThe serum concentration of Daclatasvir can be increased when it is combined with Simeprevir.Approved
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Daclatasvir.Approved
SitagliptinThe serum concentration of Sitagliptin can be increased when it is combined with Daclatasvir.Approved, Investigational
St. John's WortThe serum concentration of Daclatasvir can be decreased when it is combined with St. John's Wort.Approved, Investigational, Nutraceutical
StiripentolThe serum concentration of Daclatasvir can be increased when it is combined with Stiripentol.Approved
SulfasalazineThe serum concentration of Sulfasalazine can be increased when it is combined with Daclatasvir.Approved
SulfisoxazoleThe metabolism of Daclatasvir can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
SumatriptanThe serum concentration of Sumatriptan can be increased when it is combined with Daclatasvir.Approved, Investigational
TelaprevirThe serum concentration of Daclatasvir can be increased when it is combined with Telaprevir.Approved, Withdrawn
TelithromycinThe serum concentration of Daclatasvir can be increased when it is combined with Telithromycin.Approved
TetracyclineThe serum concentration of Tetracycline can be increased when it is combined with Daclatasvir.Approved, Vet Approved
TiclopidineThe metabolism of Daclatasvir can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Daclatasvir can be decreased when it is combined with Tocilizumab.Approved
TopiramateThe serum concentration of Topiramate can be increased when it is combined with Daclatasvir.Approved
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Daclatasvir.Approved, Investigational
VecuroniumThe serum concentration of Vecuronium can be increased when it is combined with Daclatasvir.Approved
VemurafenibThe serum concentration of Daclatasvir can be decreased when it is combined with Vemurafenib.Approved
VenlafaxineThe serum concentration of Venlafaxine can be increased when it is combined with Daclatasvir.Approved
VerapamilThe serum concentration of Verapamil can be increased when it is combined with Daclatasvir.Approved
VincristineThe excretion of Vincristine can be decreased when combined with Daclatasvir.Approved, Investigational
VoriconazoleThe serum concentration of Daclatasvir can be increased when it is combined with Voriconazole.Approved, Investigational
ZidovudineThe serum concentration of Zidovudine can be increased when it is combined with Daclatasvir.Approved
ZiprasidoneThe metabolism of Daclatasvir can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  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. 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. 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. 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. 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. 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. 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. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
  9. American Liver Foundation: Advances in Medications to Treat Hepatitis C [Link]
External Links
KEGG Drug
D10105
PubChem Compound
25154714
PubChem Substance
310265027
ChemSpider
24609522
BindingDB
50387084
ChEBI
82977
ChEMBL
CHEMBL2023898
PharmGKB
PA166128167
RxList
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Daclatasvir
ATC Codes
J05AX14 — Daclatasvir
AHFS Codes
  • 08:18.40.24 — HCV Replication Complex Inhibitors
FDA label
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedPreventionChronic Hepatitis C Virus (HCV) Infection1
1CompletedNot AvailableChronic Hepatitis C Virus (HCV) Infection1
1CompletedNot AvailableDiabetes Mellitus (DM) / Hepatitis C Viral Infection / Insulin Resistance1
1CompletedNot AvailableHealthy Volunteers2
1CompletedNot AvailableHepatic Insufficiency1
1CompletedNot AvailableHepatitis C Viral Infection3
1CompletedNot AvailableHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV)1
1CompletedBasic ScienceHepatitis C Infection1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentHepatitis C Viral Infection1
1, 2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
2CompletedDiagnosticHCV-HIV Co-Infection1
2CompletedTreatmentCHC / Chronic Hepatitis C Virus (HCV) Infection / HCV / Hepatitis C Viral Infection1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection7
2CompletedTreatmentHIV-HCV1
2CompletedTreatmentHepatitis C Infection4
2CompletedTreatmentHepatitis C Viral Infection2
2CompletedTreatmentHepatitis C Virus (HCV)5
2CompletedTreatmentHepatitis C Virus (HCV) / Hepatitis C Virus Infection1
2CompletedTreatmentHepatitis C Virus Genotype 4 Infection1
2RecruitingTreatmentHepatitis C Viral Infection / Hepatitis, Chronic1
2TerminatedTreatmentHepatitis C Viral Infection1
2WithdrawnTreatmentEnd-Stage Renal Disease (ESRD) / Impaired Renal Function1
2WithdrawnTreatmentHepatitis C Viral Infection2
2WithdrawnTreatmentHepatitis C Virus (HCV)1
2WithdrawnTreatmentHepatitis C Virus Genotype 4 Infection1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2, 3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / HBV Coinfection / Hepatitis B Reactivation1
3CompletedBasic ScienceChronic Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Genotype 3 Hepatitis C Virus / Hepatitis C Virus (HCV)1
3CompletedTreatmentHepatitis C Genotype 41
3CompletedTreatmentHepatitis C Viral Infection13
3CompletedTreatmentHepatitis C Viral Infection / Liver Cirrhosis1
3CompletedTreatmentHepatitis C Virus (HCV)4
3CompletedTreatmentHepatitis C Virus Infection2
3CompletedTreatmentHepatitis C, Genotype 11
3Not Yet RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatocellular,Carcinoma1
3RecruitingTreatmentHepatitis C Viral Infection1
3RecruitingTreatmentHepatitis C Virus Infection, Response to Therapy of / Human Immunodeficiency Virus (HIV)1
3WithdrawnTreatmentHepatitis C Viral Infection1
4Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Chronic Renal Failure (CRF)1
4Active Not RecruitingTreatmentHepatitis C Viral Infection1
4Active Not RecruitingTreatmentHepatitis C Viral Infection / Liver Cirrhosis1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
4CompletedTreatmentHepatitis C Viral Infection1
4Not Yet RecruitingTreatmentAntiviral Drug Adverse Reaction1
4Not Yet RecruitingTreatmentDrug Use / Hepatitis C Viral Infection1
4WithdrawnTreatmentChronic Hepatitis C Virus (HCV) Infection1
Not AvailableCompletedNot AvailableChronic Hepatitis C (Disorder)1
Not AvailableCompletedNot AvailableChronic Hepatitis C Virus (HCV) Infection / Liver Cirrhosis1
Not AvailableCompletedNot AvailableHepatitis C Viral Infection1
Not AvailableEnrolling by InvitationNot AvailableHepatitis C Viral Infection1
Not AvailableNo Longer AvailableNot AvailableChronic Hepatitis C Virus (HCV) Infection2
Not AvailableNot Yet RecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableNot Yet RecruitingNot AvailableHepatitis C Viral Infection3
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
Not AvailableRecruitingScreeningChronic Hepatitis C Virus (HCV) Infection1
Not AvailableRecruitingTreatmentHCV Coinfection1
Not AvailableWithdrawnNot AvailableHepatitis C Viral Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral30 mg
TabletOral30 mg/1
TabletOral60 mg/1
TabletOral60 mg
TabletOral90 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8900566No2007-08-082027-08-08Us
US8642025No2007-08-112027-08-11Us
US8629171No2011-06-132031-06-13Us
US8329159No2008-04-132028-04-13Us
US9421192No2007-08-082027-08-08Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely soluble (>700 mg/mL)FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00852 mg/mLALOGPS
logP4.67ALOGPS
logP4.18ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)11.15ChemAxon
pKa (Strongest Basic)6.09ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area174.64 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity201.82 m3·mol-1ChemAxon
Polarizability83.91 Å3ChemAxon
Number of Rings6ChemAxon
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 valine and derivatives. These are compounds containing valine or a derivative thereof resulting from reaction of valine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Valine and derivatives
Alternative Parents
Biphenyls and derivatives / Alpha amino acid amides / Phenylimidazoles / N-acylpyrrolidines / Tertiary carboxylic acid amides / Methylcarbamates / Heteroaromatic compounds / Organic carbonic acids and derivatives / Azacyclic compounds / Organopnictogen compounds
show 4 more
Substituents
Valine or derivatives / Alpha-amino acid amide / Biphenyl / 5-phenylimidazole / 4-phenylimidazole / N-acylpyrrolidine / Monocyclic benzene moiety / Benzenoid / Methylcarbamate / Azole
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
carbamate ester, imidazoles, biphenyls, carboxamide, valine derivative (CHEBI:82977)

Targets

1. Nonstructural Protein 5A (NS5A)
Kind
Protein
Organism
Hepatitis C Virus (HCV)
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Gao M: Antiviral activity and resistance of HCV NS5A replication complex inhibitors. Curr Opin Virol. 2013 Oct;3(5):514-20. doi: 10.1016/j.coviro.2013.06.014. Epub 2013 Jul 27. [PubMed:23896281]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
References
  1. 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]

Drug created on September 16, 2015 15:59 / Updated on August 15, 2018 09:56