Daclatasvir

Approved Indications:

• Chronic Hepatitis C Virus (HCV) Infection:
• Treatment of chronic HCV genotype 1, 2, 3, and 4 infections in adults.
• Used in combination with other direct-acting antivirals (DAAs) such as sofosbuvir.
• Indicated for treatment-naïve and treatment-experienced patients, including those with compensated cirrhosis.
• May be used in patients with HIV co-infection.

Clinically Accepted Off-label Uses:

• Treatment in special populations including patients with renal impairment.
• Use in patients with post-liver transplant HCV recurrence.
• Occasionally combined with ribavirin in specific difficult-to-treat genotypes or cases.

Adults:

• Standard Dose: 60 mg orally once daily.
• When used with sofosbuvir: 60 mg daily for 12 weeks; duration may vary based on genotype and patient characteristics.
• Dose adjustments generally not required for mild to moderate hepatic impairment.
• Duration of treatment depends on genotype, viral load, presence of cirrhosis, and prior treatment history.

Special Populations:

• Hepatic Impairment: No dose adjustment for mild to moderate impairment; insufficient data in severe impairment; use with caution.
• Renal Impairment: No dose adjustment necessary in mild to moderate impairment; safety data limited in severe renal impairment.
• Elderly: No dose adjustment needed.
• Pediatrics: Safety and efficacy not established in patients under 18 years.

Route of Administration:

• Oral, with or without food.

Daclatasvir is a potent, selective inhibitor of the hepatitis C virus non-structural protein 5A (NS5A), a multifunctional viral phosphoprotein essential for viral RNA replication and assembly of the viral replication complex. By binding to NS5A, daclatasvir disrupts viral replication and virion assembly, leading to suppression of HCV replication and reduction of viral load, which facilitates clearance of the virus in infected individuals.

Absorption:

• Rapid oral absorption with peak plasma concentrations reached approximately 1–2 hours post-dose.
• Oral bioavailability is high and not significantly affected by food.

Distribution:

• Highly protein bound (~99%).
• Extensive distribution to the liver, the primary site of HCV replication.

Metabolism:

• Metabolized primarily by cytochrome P450 CYP3A4 enzymes.

Elimination:

• Excreted mainly via feces (~88%), with minimal renal excretion (<1%).
• Minor metabolism to inactive metabolites.

Half-life:

• Terminal elimination half-life of approximately 12–15 hours.

Onset of Action:

• Viral load reduction generally observed within days of therapy initiation.

• Pregnancy:
• No established FDA pregnancy category.
• Animal studies have shown no significant teratogenic effects.
• Use only if potential benefits justify potential risks.
• Effective contraception recommended during treatment.
• Lactation:
• It is unknown whether daclatasvir is excreted in human milk.
• Caution advised; breastfeeding not recommended during therapy.

• Primary Class: Antiviral agent
• Subclass: Direct-acting antiviral (DAA), NS5A inhibitor

• Known hypersensitivity to daclatasvir or any component of the formulation.
• Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) that significantly reduce plasma levels.
• Use with amiodarone when combined with sofosbuvir due to risk of serious bradycardia.

• Risk of Hepatitis B Virus (HBV) Reactivation: Monitor patients with current or past HBV infection.
• Bradycardia Risk: When combined with sofosbuvir and amiodarone, severe bradycardia and heart block have been reported.
• Liver Function Monitoring: Recommended during treatment, especially in patients with advanced liver disease.
• Drug Interactions: Careful monitoring required with drugs affecting CYP3A4 enzyme activity.
• Severe Renal Impairment: Limited data; use with caution.

Common Adverse Effects:

• Headache
• Fatigue
• Nausea
• Diarrhea
• Insomnia

Serious and Rare Side Effects:

• Elevated liver enzymes (transaminases)
• Hypersensitivity reactions (rash, angioedema, anaphylaxis)
• Bradycardia (when combined with amiodarone and sofosbuvir)

Severity and Timing:

• Most adverse effects are mild to moderate and occur within the first weeks of treatment.
• Serious events are rare but require prompt medical attention.

• CYP3A4 Substrate: Daclatasvir plasma levels affected by CYP3A4 inhibitors (e.g., ketoconazole increases levels) and inducers (e.g., rifampin decreases levels).
• P-glycoprotein: Substrate; inducers or inhibitors can affect concentrations.
• Amiodarone + Sofosbuvir: Risk of serious bradycardia; concomitant use contraindicated or requires close monitoring.
• No significant food interactions; can be administered with or without meals.
• Avoid St. John’s Wort (CYP3A4 inducer) as it decreases daclatasvir effectiveness.

• Current HCV treatment guidelines recommend daclatasvir plus sofosbuvir as a pan-genotypic regimen, especially where newer DAAs are unavailable or in certain clinical scenarios.
• Recent updates highlight caution with concomitant amiodarone use due to bradycardia risk.
• Expanded indications include use in cirrhotic patients and HIV co-infection.
• WHO and EASL recommend daclatasvir-containing regimens as effective and well-tolerated options.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light; keep in original container.
• Do not freeze.
• Handle with care; no reconstitution needed as this is an oral tablet.