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 [A19642]. High proportion of the drug in the plasma (greater than 97%) is in the unchanged form.
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 has, however, been implicated in rare instances of acute decompensation of HCV related cirrhosis. The role of daclatasvir and the other HCV antivirals in this syndrome, however, is unclear. The liver injury usually arises within 2 to 6 weeks of starting therapy, but can occur later and even after discontinuation of therapy. The injury is marked by worsening jaundice and signs of hepatic failure. Lactic acidosis may be present early. In most but not all instances, the serum enzymes increase minimally if at all, despite the worsening hepatic failure. Several instances have resulted in death or need for emergency liver transplantation. For this reason, patients with cirrhosis undergoing antiviral therapy with potent direct acting agents should be monitored carefully, particularly during the first few weeks of treatment.
Finally, reactivation of hepatitis B has occurred in rare patients being treated for chronic hepatitis C some of whom had received daclatasvir. The relationship of HBV reactivation to the antiviral treatment of HCV infection is not clear, but it may be due to clearance of HCV replication which may allow an increase in HBV levels.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury in patients with cirrhosis or preexisting hepatitis B virus coinfection).
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.
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.
2'-AZIDO SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
申请人：Girijavallabhan Vinay
公开号：US20140206640A1
公开（公告）日：2014-07-24
The present invention relates to 2′-Azido Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R
1
, R
2
and R
3
are as defined herein. The present invention also relates to compositions comprising at least one 2′-Azido Substituted Nucleoside Derivative, and methods of using the 2′-Azido Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
[EN] COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS<br/>[FR] ASSOCIATIONS D'INHIBITEURS DU VIRUS DE L'HÉPATITE C
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2015005901A1
公开（公告）日：2015-01-15
The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
[EN] HEPATITIS C VIRUS INHIBITORS<br/>[FR] INHIBITEURS DU VIRUS DE L'HÉPATITE C
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2011075439A1
公开（公告）日：2011-06-23
The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
2'-CYANO SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF USEFUL FOR THE TREATMENT OF VIRAL DISEASES
申请人：Girijavallabhan Vinay
公开号：US20140161770A1
公开（公告）日：2014-06-12
The present invention relates to 2′-Cyano Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R
1
, R
2
and R
3
are as defined herein. The present invention also relates to compositions comprising at least one 2′-Cyano Substituted Nucleoside Derivative, and methods of using the 2′-Cyano Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
