Daclatasvir

738.89

738.88

1592732-453-0

LI2427F9CI

C114981

J05AP07|J - Antiinfectives for systemic use

29332900

175

5.44

1.249

1071.2±65.0 °C(Predicted)

601.7±34.3 °C

1.595

H2O: Freely soluble (>700 mg/mL)

24/25

P260, P261, P264, P271, P272, P280, P302+P352, P304+P340, P305+P351+P338, P312, P314, P321, P333+P313, P337+P313, P363, P403+P233, P405, P501

H317

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.

In large randomized controlled trials, daclatasvir was not associated with serum enzyme elevations during therapy. A difficulty in assessing side effects of daclatasvir and other anti-HCV agents, however, is that they are never used as monotherapy, but are also combined with agents active against other HCV targets, such as the viral protease (NS3) or polymerase (NS5B). Daclatasvir is also commonly used in combination with the more traditional agents used for hepatitis C, such as peginterferon and ribavirin, both of which have prominent adverse effects. In combination with asunaprevir (an HCV protease inhibitor), daclatasvir was associated with serum ALT elevations in 3% to 11% of patients and with several instances of acute hypersensitivity and hepatitis, some of which were severe. The cause of the hypersensitivity reaction, however, appeared to be asunaprevir. In combination with sofosbuvir, daclatasvir has not been associated with serum enzyme elevations or with clinically apparent liver injury.

Daclatasvir is highly protein bound (99%).

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.|FDA Label|Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1)., , For HCV genotype specific activity, see sections 4.4 and 5.1.,|Treatment of chronic hepatitis C

Daclatasvir is an orally available antiviral agent that inhibits the NS5A region of the hepatitis C virus (HCV) and is used in combination with other oral antiviral agents to treat chronic hepatitis C. Elevations in serum enzyme levels during daclatasvir therapy are uncommon, and it has yet to be convincingly implicated in cases of clinically apparent liver injury with jaundice. Nevertheless, and for unknown reasons, successful all-oral regimens of antiviral therapy in patients with chronic hepatitis C and cirrhosis is occasionally complicated by hepatic decompensation and may cause reactivation of hepatitis B in susceptible patients coinfected with the hepatitis B virus (HBV).

Hepatitis C Agents

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.

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

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.

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.

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.

BMS-790052

Human drugs -> Daklinza -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients