Daclatasvir

Usage

• Daclatasvir is an antiviral medication specifically designed to treat chronic hepatitis C virus (HCV) infection. It is effective against HCV genotypes 1, 3, and 4.
• Pharmacological Classification: Direct-acting antiviral (DAA), specifically an HCV NS5A inhibitor.
• Mechanism of Action: Daclatasvir targets the NS5A protein of the HCV, a crucial component for viral replication and assembly. By binding to NS5A, daclatasvir disrupts these processes, effectively inhibiting viral reproduction.

Alternate Names

• Daklinza (brand name)

How It Works

• Pharmacodynamics: Daclatasvir’s primary effect is inhibiting HCV replication. It specifically targets the NS5A protein, which plays a key role in both RNA replication and the assembly of new viral particles (virions).
• Pharmacokinetics:
  • Absorption: Daclatasvir is well-absorbed orally, reaching peak plasma concentrations within 1-2 hours. Food does not significantly affect absorption.
  • Metabolism: Primarily metabolized by the cytochrome P450 CYP3A4 enzyme.
  • Elimination: Excreted mainly through the biliary route into the feces, with a small fraction eliminated through the kidneys. The elimination half-life is approximately 12-15 hours, achieving steady-state after about 4 days of once-daily dosing.
• Mode of Action: Daclatasvir directly binds to the N-terminus within Domain 1 of the HCV NS5A protein. This binding interferes with the essential functions of NS5A in viral RNA replication and virion assembly.
• Elimination Pathways: Primarily hepatic excretion via the biliary route into feces. A small portion undergoes renal excretion.

Dosage

Standard Dosage

Adults:

• 60 mg orally once daily, taken with or without food.
• Administered in combination with other antiviral agents (sofosbuvir, with or without ribavirin).
• Treatment duration: typically 12-24 weeks, depending on the HCV genotype and the presence or absence of cirrhosis.

Children:

• The safety and efficacy of daclatasvir in children younger than 18 years have not been established. Dosage recommendations are not available for pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is typically needed.
• Patients with Renal Impairment: No dose adjustment is necessary.
• Patients with Hepatic Dysfunction: No dose adjustment is needed, even in patients with severe hepatic impairment (Child-Pugh C).
• Patients with Comorbid Conditions: Careful monitoring is recommended for patients with diabetes, cardiovascular disease, or HBV co-infection.

Clinical Use Cases

Daclatasvir is not indicated for use in specific clinical settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations. Its use is restricted to the treatment of chronic HCV infection.

Dosage Adjustments

• CYP3A4 Inhibitors: Reduce daclatasvir dose to 30 mg once daily when co-administered with strong CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, ketoconazole).
• CYP3A4 Inducers: Increase daclatasvir dose to 90 mg once daily when co-administered with moderate CYP3A4 inducers (e.g., efavirenz, etravirine, modafinil). Daclatasvir is contraindicated with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort).

Side Effects

Common Side Effects:

• Headache
• Fatigue
• Nausea
• Diarrhea

Rare but Serious Side Effects:

• Severe bradycardia (especially when co-administered with amiodarone and sofosbuvir)
• Hepatitis B reactivation in patients with HBV co-infection

Long-Term Effects:

• Long-term side effects are not well-characterized but may include potential liver complications in patients with pre-existing cirrhosis.

Adverse Drug Reactions (ADR):

• Severe bradycardia requiring urgent medical attention.
• Signs of hepatic decompensation (jaundice, ascites, hepatic encephalopathy) in patients with cirrhosis.

Contraindications

• Hypersensitivity to daclatasvir
• Concurrent use with strong CYP3A4 and P-glycoprotein (P-gp) inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort)
• Co-administration with sofosbuvir and amiodarone
• Pregnancy, especially when combined with ribavirin

Drug Interactions

• CYP3A4 Inhibitors: Increase daclatasvir exposure.
• CYP3A4 Inducers: Decrease daclatasvir exposure, potentially leading to treatment failure.
• Amiodarone: Increased risk of severe bradycardia when co-administered with daclatasvir and sofosbuvir.
• Other Interactions: Consult a comprehensive drug interaction database for a complete list.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated in pregnancy, particularly with ribavirin. Highly effective contraception is necessary.
• Breastfeeding: Limited information available. Not recommended when used with ribavirin.

Drug Profile Summary

• Mechanism of Action: HCV NS5A inhibitor, disrupting viral replication and assembly.
• Side Effects: Headache, fatigue, nausea, diarrhea. Rarely, severe bradycardia, HBV reactivation.
• Contraindications: Hypersensitivity, strong CYP3A4/P-gp inducers, concomitant use of amiodarone with sofosbuvir, pregnancy (especially with ribavirin).
• Drug Interactions: CYP3A4 inhibitors/inducers, amiodarone. Consult a database for a full list.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, particularly with ribavirin. Not recommended during breastfeeding, especially with ribavirin.
• Dosage: 60 mg once daily with sofosbuvir (with or without ribavirin), adjusted for drug interactions.
• Monitoring Parameters: Liver function tests, HCV RNA levels, cardiac monitoring (with amiodarone), blood glucose (in patients with diabetes).

Popular Combinations

• Sofosbuvir (with or without ribavirin)

Precautions

• General Precautions: Screen for HBV infection, monitor liver function and cardiac rhythm (with amiodarone).
• Specific Populations: Contraindicated in pregnancy (especially with ribavirin). Not recommended during breastfeeding.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Daclatasvir?

A: 60 mg orally once daily in combination with sofosbuvir (with or without ribavirin). Dose adjustments are needed for specific drug interactions.

Q2: What are the most common side effects of Daclatasvir?

A: Headache, fatigue, nausea, and diarrhea.

Q3: Can Daclatasvir be used during pregnancy?

A: No, Daclatasvir is contraindicated in pregnancy, especially when combined with ribavirin.

Q4: What is the mechanism of action of Daclatasvir?

A: It is an HCV NS5A inhibitor, preventing viral replication and assembly.

Q5: What are the major drug interactions with Daclatasvir?

A: Strong CYP3A4 inhibitors and inducers, amiodarone (when used with sofosbuvir). Consult a drug interaction database for a comprehensive list.

Q6: What is the role of NS5A in the HCV lifecycle?

A: NS5A is crucial for HCV RNA replication and the assembly of new virus particles.

Q7: How is Daclatasvir metabolized?

A: Primarily metabolized by CYP3A4.

Q8: How is Daclatasvir eliminated from the body?

A: Mainly through biliary excretion into the feces, with a small amount via renal excretion.

Q9: Can Daclatasvir be used as monotherapy?

A: No, Daclatasvir should always be used in combination with other antiviral agents for HCV treatment.