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Daclatasvir | CAS No: 1009119-64-5 | GMP-certified suppliers
A medication that, combined with sofosbuvir, treats chronic hepatitis C virus genotypes 1a, 1b, and 3 infections, improving virologic response in patients with or without cirrhosis.
Therapeutic categories
Primary indications
- 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
Product Snapshot
- Daclatasvir is an oral small molecule formulated as film-coated tablets
- It is primarily used in combination therapy for the treatment of chronic hepatitis C virus (HCV) genotypes 1a, 1b, and 3 infections
- Daclatasvir is approved for use in key regulatory markets including the United States and Canada
Clinical Overview
Pharmacologically, daclatasvir targets the nonstructural protein 5A (NS5A) of HCV, a phosphoprotein integral to the viral replication complex located on the endoplasmic reticulum membranes. NS5A plays essential cis- and trans-acting roles in viral RNA replication and virion assembly. Daclatasvir binds to the N-terminus of the D1 domain of NS5A, disrupting its interaction with host cell proteins and membranes necessary for replication complex formation. This results in inhibition of both viral RNA synthesis and assembly of infectious particles. The drug also modulates the phosphorylation status of NS5A, particularly downregulating its hyperphosphorylated form which is critical for viral replication.
Key pharmacokinetic data show that daclatasvir is administered orally in the hydrochloride salt form. It is a substrate for cytochrome P450 enzymes, particularly CYP3A4, and is involved with transporters including P-glycoprotein and organic anion transporting polypeptides (OATP1B1/1B3). This implicates potential drug–drug interactions that require consideration during therapy.
Resistance to daclatasvir is associated with specific amino acid substitutions at NS5A positions M28, Q30, L31, and Y93, with substitutions at Q30 and Y93 being most clinically relevant in genotypes 1a and 3, respectively. Resistance testing is recommended prior to initiating treatment in genotype 1a patients with cirrhosis due to increased risk of reduced susceptibility.
Safety data indicate that daclatasvir is generally well tolerated and does not significantly affect cardiac repolarization, including the QT interval, even at supratherapeutic doses. Adverse effects should be monitored in conjunction with co-administered agents.
Daclatasvir is marketed under the trade name DAKLINZA. It is utilized in various clinical contexts including patients with HIV-1 coinfection, advanced liver disease, and post-liver transplantation recurrence of HCV. Achieving sustained virologic response at 12 weeks post-treatment correlates with long-term reductions in hepatic complications and mortality.
For API procurement, quality considerations should include verification of the hydrochloride salt form, compliance with current Good Manufacturing Practices (cGMP), and thorough impurity profiling due to the complexity of synthesis and potential for polypeptide-related contaminants. Supplier qualification should ensure robust documentation enabling regulatory submissions, with attention to stability, batch-to-batch consistency, and scalability.
Identification & chemistry
| Generic name | Daclatasvir |
|---|---|
| Molecule type | Small molecule |
| CAS | 1009119-64-5 |
| UNII | LI2427F9CI |
| DrugBank ID | DB09102 |
Pharmacology
| Summary | Daclatasvir is a direct-acting antiviral agent targeting the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV), a key component of the viral replication complex responsible for RNA genome amplification and virion assembly. It inhibits HCV replication by disrupting hyperphosphorylated NS5A, thereby blocking viral RNA synthesis and infectious particle formation. This mechanism results in a decrease in serum HCV RNA levels and impairs the maintenance of the viral replication complex. |
|---|---|
| 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 . 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 . |
| 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 . 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Nonstructural protein 5A | Hepatitis C Virus | inhibitor |
ADME / PK
| 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%. |
|---|---|
| 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. |
| 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 . 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. |
| Volume of distribution | The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously. |
| Clearance | In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h. |
Formulation & handling
- Daclatasvir is formulated exclusively for oral administration as tablets, including film-coated forms.
- It is a small molecule with low water solubility and moderate lipophilicity, requiring consideration for bioavailability enhancement in formulation.
- Avoid co-administration with grapefruit and St. John's Wort due to significant CYP3A-mediated interaction risks affecting plasma levels.
Regulatory status
| Lifecycle | The API is currently under patent protection in the United States with key patents expiring between 2027 and 2031. The product is marketed in the US and Canada, indicating ongoing market exclusivity and moderate maturity in these regions. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | Daclatasvir is primarily supplied by multiple originator companies with branded products marketed mainly in the US and Canada. Several patents are in place in the United States, with expiry dates ranging from 2027 to 2031, indicating that generic competition is currently limited but may emerge progressively after these dates. The presence of multiple patents suggests ongoing protection affecting the timing and scope of generic entry. |
|---|
Safety
| 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. |
|---|
- Daclatasvir may cause adverse effects including headache, fatigue, nausea, and diarrhea
- Addition of ribavirin can increase incidence of rash, insomnia, anemia, dizziness, and somnolence
- Serious symptomatic bradycardia has been reported with concurrent use of daclatasvir, sofosbuvir, and amiodarone
Daclatasvir is a type of Anti-HCV agents
Anti-HCV agents, belonging to the pharmaceutical API category, are potent medications used in the treatment of Hepatitis C Virus (HCV) infection. Hepatitis C is a viral disease that affects the liver and can lead to severe health complications if left untreated. Anti-HCV agents work by targeting specific mechanisms involved in the replication and spread of the HCV virus within the body.
These pharmaceutical APIs are designed to inhibit various steps of the viral lifecycle, including viral entry into liver cells, viral RNA replication, and assembly of new viral particles. By disrupting these critical processes, anti-HCV agents effectively reduce the viral load in the body, slow down disease progression, and ultimately improve patient outcomes.
The development of anti-HCV agents has revolutionized the management of HCV infection, offering new hope for patients. These APIs are often used in combination with other antiviral drugs to form highly effective treatment regimens known as direct-acting antiviral (DAA) therapies. DAAs have significantly higher cure rates compared to older treatment options, such as interferon-based therapies, and are associated with fewer side effects.
The pharmaceutical industry has made significant advancements in the development of anti-HCV agents, resulting in a diverse range of APIs with varying mechanisms of action. This diversity allows healthcare professionals to tailor treatment plans based on the specific characteristics of each patient's HCV infection, maximizing the chances of successful viral eradication.
In summary, anti-HCV agents are a crucial category of pharmaceutical APIs used in the treatment of Hepatitis C. Their targeted action against the HCV virus has revolutionized the management of this chronic infection, providing more effective and better-tolerated treatment options for patients.
Daclatasvir API manufacturers & distributors
Compare qualified Daclatasvir API suppliers worldwide. We currently have 9 companies offering Daclatasvir API, with manufacturing taking place in 2 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Apino Pharma Co., Ltd. | Producer | China | China | BSE/TSE, CoA, GMP, ISO9001, MSDS, USDMF | 229 products |
| Cipla | Producer | India | India | CoA, USDMF | 164 products |
| Fuxing Long Rui Pharma | Producer | China | China | CoA, USDMF | 10 products |
| Hetero Labs | Producer | India | India | CoA, USDMF | 90 products |
| Laurus Labs | Producer | India | India | CoA, GMP, WC | 50 products |
| MSN Life Sciences | Producer | India | India | CoA, USDMF | 46 products |
| Mylan | Producer | India | India | CoA, GMP, WC | 201 products |
| SETV Global | Producer | India | India | CoA, FDA, GMP | 515 products |
| Shaoxing Hantai Pharma | Distributor | China | China | CoA | 162 products |
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