Daclavir

Indications

• Chronic hepatitis C virus infection
• HCV genotype-specific treatment regimens

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing guidelines.

Adults: Refer to the BNF for the specific dosing regimen based on the treatment indication and any concomitant medications.

Mechanism of action

Daclatasvir targets the NS5A protein of the hepatitis C virus, inhibiting its function in the viral replication complex. It does this by disrupting hyperphosphorylated NS5A proteins, which are essential for the maintenance and function of new HCV replication complexes. This inhibition leads to a reduction in intracellular viral RNA synthesis and virion assembly/secretion.

Pharmacodynamics

As a direct-acting antiviral, daclatasvir effectively reduces serum HCV RNA levels by specifically inhibiting the NS5A protein's critical functions in the replication complex. Its action leads to downregulation of the hyperphosphorylation of NS5A without prolonging the QT interval, even at doses three times greater than the maximum recommended dose.

Pharmacokinetics

Daclatasvir is well-absorbed after oral administration and reaches peak plasma concentrations within 1 to 4 hours. It has a large volume of distribution and is extensively metabolized by the liver, primarily via cytochrome P450 3A4. The drug has a long half-life, allowing for once-daily dosing. Excretion occurs mainly through feces, with minimal renal elimination.

Adverse effects

• Headache
• Nausea
• Fatigue
• Diarrhea
• Insomnia
• Elevated liver enzymes

Interactions

• CYP3A4 inducers may decrease daclatasvir levels
• CYP3A4 inhibitors may increase daclatasvir levels

Precautions

• Caution in patients with hepatic impairment
• Monitor liver function tests regularly during treatment

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Daclatasvir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether daclatasvir is excreted in human breast milk. Caution should be exercised when administering to a nursing mother.

Storage

Store below 30 degrees Celsius. Protect from moisture and light.

Formulations

• Film-coated tablets

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.