ABT-333

Absorption

Dasabuvir reaches peak plasma concentration 4 hours after administration . The absolute bioavailability of Dasabuvir is 70%.

Toxicity

The most common adverse effects of Viekira Pak either in combination with or without Ribavirin were pruritus, nausea, insomnia, and asthenia .

The Uses of ABT-333

Dasabuvir is an antiviral drug used in the treatment of chronic hepatitis C virus (HCV) infection.

Background

Dasabuvir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, 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 being the most common in the United States, and affecting 72% of all chronic HCV patients . Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Dasabuvir. Dasabuvir is a non-nucleoside NS5B inhibitor which binds to the palm domain of NS5B and induces a conformational change which renders the polymerase unable to elongate viral RNA . The binding sites for non-nucleoside NS5B inhibitors are poorly conserved across HCV genotypes leading to the restriction of Dasabuvir's use to genotype 1 only.
In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Dasabuvir as first line therapy in combination with Ombitasvir, Paritaprevir, and Ritonavir for genotype 1b and with Ribavirin for genotype 1a of Hepatitis C . Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir, and Ribavirin are used with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of 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 .
Dasabuvir is available as a fixed dose combination product with Ombitasvir, Paritaprevir, and Ritonavir (tradename Viekira Pak) used for the treatment of chronic Hepatitis C. Approved in December 2014 by the FDA, Viekira Pak is indicated for the treatment of HCV genotype 1a with Ribavirin or genotype 1b without Ribavirin . When combined together, Dasabuvir Ombitasvir, Paritaprevir, and Ritonavir as the combination product Viekira Pak have been shown to achieve a SVR of 100% for genotype 1b and 89% or 95% for genotype 1a after 12 weeks or 24 weeks of treatment including Ribavirin.

Indications

Dasabuvir, in combination with Ombitasvir, Paritaprevir, and Ritonavir (as Viekira Pak) is indicated for the treatment of patients with HCV genotype 1a with Ribavirin or genotype 1b without Ribavirin including those with compensated cirrhosis .

Definition

ChEBI: A member of the class of pyrimidone, which is (as the monohydrate of its sodium salt) in combination with ombitasvir, paritaprevir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as c rrhosis of the liver.

Pharmacokinetics

Dasabuvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1 .

Clinical Use

Treatment of chronic hepatitis C infection

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: avoid concomitant use with clarithromycin and telithromycin; concentration possibly reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration reduced by carbamazepine - avoid; concentration possibly reduced by fosphenytoin, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration of both drugs increased with ketoconazole and possibly itraconazole and posaconazole - avoid.
Diuretics: concentration of furosemide increased (reduce furosemide dose).
Immunosuppressants: increases concentration of ciclosporin (reduce ciclosporin dose by a fifth); everolimus (avoid); sirolimus and tacrolimus (reduce dose and use only if benefit outweighs risk - see SPC).
Lipid-regulating drugs: avoid with atorvastatin, gemfibrozil and simvastatin; concentration of rosuvastatin increased (reduce dose of rosuvastatin).
Oestrogens: avoid concomitant use with ethinylestradiol.

Metabolism

Dasabuvir is predominantly metabolized by CYP2C8, and to a lesser extent by CYP3A .

Metabolism

Dasabuvir is mainly metabolised by CYP2C8 and to a lesser extent by CYP3A. Seven metabolites were identified in plasma. The most abundant plasma metabolite was M1, which represented 21% of drugrelated radioactivity (AUC) in circulation following single dose; it is formed via oxidative metabolism predominantly by CYP2C8.
Following a 400 mg 14C-dasabuvir dose, approximately 94% of the radioactivity was recovered in faeces with limited radioactivity (approximately 2%) in urine. Unchanged dasabuvir accounted for 26.2% and M1 for 31.5% of the total dose in faeces. M1 is mainly cleared through direct biliary excretion with the contribution of UGT-mediated glucuronidation and, to a small extent, oxidative metabolism.