Daclatasvir

Daclatasvir is a direct-acting antiviral agent against Hepatitis C Virus (HCV) used for the treatment of chronic HCV genotype 1 and 3 infection. Hepatitis C is an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 and affecting 72% of all chronic HCV patients . Daclatasvir was the first drug with demonstrated safety and therapeutic efficacy in treating HCV genotype 3 without the need for co-administration of interferon or Ribavirin. It exerts its antiviral action by preventing RNA replication and virion assembly via 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. Daclatasvir is shown to target both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status . The most common critical NS5A amino acid substitutions that led to reduced susceptibility to daclatasvir therapy occured at position Q30 (Q30H/K/R) and M28 in genotype 1a patients and Y93H in genotype 3 patients.

According to 2017 American Association for the Study of Liver Diseases (AASLD), 60mg of daclatasvir is recommended with 400mg Sofosbuvir for genotype 1a/b patients with or without cirrhosis as second-line therapy. The same dosing regimen can be used as first-line therapy in patients with genotype 3 without cirrhosis and second-line therapy in genotype 3 patients with compensated cirrhosis. Combination therapies that include daclatasir can be used for challenging-to-treat patients who have HIV-1 coinfection, advanced cirrhosis, or post-liver transplant recurrence of HCV . The therapy is intended to cure or achieve a sustained virologic response (SVR12), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .

The SVR12 in HCV genotype 1a-infected treatment-naïve subjects without and with cirrhosis undergoing daclatasvir and Sofosbuvir therapy were 88% and 99%, respectively . The same dosing regimen in treatment-naïve patients with HCV genotype 3 infection with or without cirrhosis achieved SVR12 rates of 71% and 98%, respectively .

Daclatasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

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.

• Chronic Hepatitis C Genotype 1
• Chronic Hepatitis C Virus (HCV) Infection
• Chronic hepatitis C genotype 2
• Chronic hepatitis C genotype 3

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.

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 .

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%.

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.

Daclatasvir is highly protein bound (99%).

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.

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.

In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h.

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.

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of daclatasvir, which may increase its serum concentration. Dose changes may be necessary.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of daclatasvir and may reduce its serum concentration. Co-administration of daclatasvir with St. John's Wort is contraindicated.
• Take with or without food. Daclatasvir AUC and Cmax are slightly reduced when administered with food.

• The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
• Dose modification, interruption and discontinuation: Dose modification of Daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daclatasvir must not be given as monotherapy.
• There are no virologic treatment stopping rules that apply to the combination of Daclatasvir with Sofosbuvir.
• Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daclatasvir, Peginterferon alfa and Ribavirin.

• Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4): The dose of Daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
• Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
• Missed doses: Patients should be instructed that, if they miss a dose of Daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.