Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C40H50N8O6 |
Molecular Weight | 738.875 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)[C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C
InChI
InChIKey=FKRSSPOQAMALKA-CUPIEXAXSA-N
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
Molecular Formula | C40H50N8O6 |
Molecular Weight | 738.875 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Daclatasvir (BMS-790052) is a direct-acting antiviral agent against Hepatitis C Virus (HCV) used for the treatment of chronic HCV genotype 3 infection. Daclatasvir prevents RNA replication and virion assembly by 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.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3307224 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27643675 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | DAKLINZA Approved UseDAKLINZA is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection [see Dosage and Administration (2) and Clinical Studies (14) Launch Date2015 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1295 ng/mL |
60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
1582 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29353349/ |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
291 ng/mL |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
257 ng/mL |
10 mg 1 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
610 ng/mL |
30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
734 ng/mL |
30 mg 1 times / day steady-state, oral dose: 30 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
148 ng/mL |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
1226 ng/mL |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
16.4 ng/mL |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2816 ng/mL |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11475 ng × h/mL |
60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
15666 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29353349/ |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2371 ng × h/mL |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2453 ng × h/mL |
10 mg 1 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
4548 ng × h/mL |
30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
6275 ng × h/mL |
30 mg 1 times / day steady-state, oral dose: 30 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
9680 ng × h/mL |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
13471 ng × h/mL |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
162 ng × h/mL |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
31793 ng × h/mL |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
13.5 h |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
13.5 h |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
9.83 h |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
11 h |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
DACLATASVIR plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1% |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
DACLATASVIR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
100 mg 1 times / day multiple, oral Highest studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: |
unhealthy, 44 years (range: 34-49 years) n = 4 Health Status: unhealthy Condition: HCV infection Age Group: 44 years (range: 34-49 years) Sex: M+F Population Size: 4 Sources: |
Other AEs: Headache, Diarrhea... Other AEs: Headache (25%) Sources: Diarrhea (25%) Abdominal pain (25%) |
200 mg single, oral Highest studied dose |
healthy, adult |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Abdominal pain | 25% | 100 mg 1 times / day multiple, oral Highest studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: |
unhealthy, 44 years (range: 34-49 years) n = 4 Health Status: unhealthy Condition: HCV infection Age Group: 44 years (range: 34-49 years) Sex: M+F Population Size: 4 Sources: |
Diarrhea | 25% | 100 mg 1 times / day multiple, oral Highest studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: |
unhealthy, 44 years (range: 34-49 years) n = 4 Health Status: unhealthy Condition: HCV infection Age Group: 44 years (range: 34-49 years) Sex: M+F Population Size: 4 Sources: |
Headache | 25% | 100 mg 1 times / day multiple, oral Highest studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: |
unhealthy, 44 years (range: 34-49 years) n = 4 Health Status: unhealthy Condition: HCV infection Age Group: 44 years (range: 34-49 years) Sex: M+F Population Size: 4 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 13.0 |
no [IC50 >40 uM] | |||
Page: 13.0 |
no [IC50 >40 uM] | |||
Page: 13.0 |
no [IC50 >40 uM] | |||
Page: 13.0 |
no [IC50 >40 uM] | |||
Page: 13.0 |
no [IC50 >40 uM] | |||
Page: 13.0 |
no [IC50 >40 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206843Orig1s000PharmR.pdf#page=132 Page: 132.0 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206843Orig1s000PharmR.pdf#page=132 Page: 132.0 |
no | |||
Page: 13.0 |
no | |||
Page: 13.0 |
yes | |||
yes | unlikely (co-administration study) Comment: interaction between steady-state DCV and single-dose midazolam (a sensitive CYP3A4 probe) demonstrated that DCV is unlikely to impact the exposure of concomitant medications through CYP3A4-related mechanisms; midazolam exposure was minimally decreased (13%) during co-administration Page: 132.0 |
|||
yes | unlikely (co-administration study) Comment: interaction between steady-state DCV and single-dose midazolam (a sensitive CYP3A4 probe) demonstrated that DCV is unlikely to impact the exposure of concomitant medications through CYP3A4-related mechanisms; midazolam exposure was minimally decreased (13%) during co-administration Page: 132.0 |
|||
yes | weak (co-administration study) Comment: The co-administration of DCV with digoxin, both agents at steady-state, resulted in a 27% increase in digoxin AUC during co-administration Page: 13.0 |
|||
yes | yes (co-administration study) Comment: co-administration with DCV at steady-state, single-dose rosuvastatin exposure was increased (C max, two-fold; AUC, 58% increase Page: 13.0 |
|||
yes | yes (co-administration study) Comment: co-administration with DCV at steady-state, single-dose rosuvastatin exposure was increased (C max, two-fold; AUC, 58% increase Page: 13.0 |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes | likely (co-administration study) Comment: coadministration with CYP3A4 inhibitors/inducers are likely to affect drug concentration Page: 132.0 |
|||
Page: 13.0 |
yes | no (co-administration study) Comment: cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir Page: 13.0 |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206843Orig1s000PharmR.pdf#page=25 Page: 25.0 |
PubMed
Title | Date | PubMed |
---|---|---|
Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. | 2010 Sep |
|
Inhibition of hepatitis C virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug. | 2014 |
|
The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance. | 2014 Jun |
|
Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir. | 2014 Mar 13 |
|
Changing the face of hepatitis C management - the design and development of sofosbuvir. | 2015 |
Sample Use Guides
The recommended dosage is 60 mg, taken orally, once daily in combination with sofosbuvir for 12 weeks. Drug may be taken with or without food.
Route of Administration:
Oral
Daclatasvir had a median EC50 value of 0.2 nM against hybrid replicons containing genotype 3a subject-derived NS5A sequences without detectable daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93 with a median EC50 value of 13.5 nM (range, 1.3-50 nM). Similarly, the EC50 values of daclatasvir against 3 genotype 3b and 1 genotype 3i subject-derived NS5A sequences with polymorphisms (relative to a genotype 3a reference) at positions 30 or 31 were ≥3620 nM. The median EC50 values of daclatasvir for genotypes 1a, 1b, 2, 4, and 5 subject-derived NS5A hybrid replicons were 0.008 nM (range, 0.002-2409 nM, n=40), 0.002 nM (range, 0.0007-10 nM, n=42), 16 nM (range, 0.005-60 nM, n=16), 0.025 nM (range, 0.001-158 nM, n=14), and 0.004 nM (range, 0.003-0.019 nM, n=3), respectively. The EC50 value against a single HCV genotype 6 derived replicon was 0.054 nM.
Substance Class |
Chemical
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Record UNII |
LI2427F9CI
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WHO-ATC |
J05AP07
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WHO-ATC |
J05AX14
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NCI_THESAURUS |
C281
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N0000191256
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N0000185503
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PRIMARY | P-Glycoprotein Inhibitors [MoA] | ||
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N0000190113
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PRIMARY | Breast Cancer Resistance Protein Inhibitors [MoA] | ||
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Daclatasvir
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SUB75341
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N0000190108
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PRIMARY | Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA] | ||
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DB09102
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N0000190107
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PRIMARY | Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA] | ||
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CHEMBL2023898
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Daclatasvir
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Related Record | Type | Details | ||
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METABOLIC ENZYME -> SUBSTRATE | |||
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BINDER->LIGAND |
BINDING
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EXCRETED UNCHANGED |
FECAL
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EXCRETED UNCHANGED |
URINE
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TRANSPORTER -> SUBSTRATE | |||
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SALT/SOLVATE -> PARENT |
Related Record | Type | Details | ||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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MULTIPLE DOSE |
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