ABT-267

Absorption

Ombitasvir reaches peak plasma concentration 5 hours after administration . It has an absolute bioavailability of 48%. Taking ombitasvir with high or normal fat meals increases exposure by 1.76 or 1.82 fold respectively.

Toxicity

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

Description

Ombitasvir hydrate is a NS5A non-nucleoside polymerase inhibitor which is approved as part of a four drug combination for the treatment of adults with genotype 1 hepatitis C virus infection including those with compensated cirrhosis. The four drug combination treatment consists of ombitasvir, paritaprevir (XXVII), ritonavir, and dasabuvir (X). This combination treatment is marketed as Viekira Pak and was developed by Abbvie as an all oral treatment that eliminates the need for pegylated interferon- a injections.

The Uses of ABT-267

Ombitasvir is a pharmaceutical drug that is used in the treatment of hepatitis C virus in patients with HCV genotype 1 infection. It inhibits an important viral phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion.

Indications

When used in combination with Paritaprevir and Ritonavir (as the fixed dose product Technivie), Ombitasvir is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis .
When used in combination with Paritaprevir, Ritonavir, and Dasabuvir (as the fixed dose product Viekira Pak), Ombitasvir is indicated for the treatment of HCV genotype 1b and ,when combined with Ribavirin, for the treatment of HCV genotype 1a

Background

Ombitasvir 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 Ombitasvir. Ombitasvir is an inhibitor of NS5A, a protein essential for viral replication and virion assembly . The barrier for develoment of resistance to NS5A inhibitors is lower than that of NS5B inhibitors, another class of DAAs .
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 Ombitasvir as a first line therapy option when used in combination with other antivirals for genotypes 1a, 1b, and 4 . Depending on the genotype, Ombitasvir is often used in combination with other antivirals such as Dasabuvir, Paritaprevir, Ritonavir, and Ribavirin with the intent to cure, or achieve a sustained virologic response (SVR), 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 . Treatment with direct acting antivirals such as Ombitasvir is associated with very minimal side effects, with the most common being headache and fatigue . Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects .
Ombutasvir first came on the market as a fixed-dose combination product with Dasabuvir, Paritaprevir, and Ritonavir as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.
Ombutasvir is also available as a fixed-dose combination product with Paritaprevir and Ritonavir as the FDA- and Health Canada-approved product Technivie. First approved in July 2015, Technivie is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.
In Canada, Ombutasvir is also available as a fixed-dose combination product with Dasabuvir, Paritaprevir, and Ritonavir as the Health Canada-approved, commercially available product Holkira Pak. First approved in January 2015, Holkira Pak is indicated for the treatment of HCV genotype 1b with or without cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a with or without cirrhosis.

Definition

ChEBI: A dipeptide derivative which is used which is in combination with dasabuvir sodium hydrate, paritaprevir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver.

Pharmacokinetics

Ombitasvir is classified as a direct acting antiviral and acts against HCV to inhibit viral replication .

Clinical Use

Treatment of chronic hepatitis C infection

Synthesis

Alkylation of 1-(4-nitrophenyl)ethanone (209) with 2-bromo-1-(4-nitrophenyl)ethanone (208) in the presence of zinc chloride produced diketone 210 in 61% yield. Asymmetric reduction of the diketone using N,N-diethylaniline borane with (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (211) and trimethoxyborate gave diol 212 in 61% yield and 99.3% ee. The diol was then treated with methanesulfonic anhydride to generate the corresponding bis-mesylate which was reacted with 4-tert-butylaniline to give pyrrolidine 213 in 51% yield over the two steps. Hydrogenolysis of the nitro groups was accomplished using Raney nickel catalyst to give bis-aniline 214. Separately, (L)-valine (216) was reacted with methyl chloroformate to give the corresponding methyl carbamate in 90% yield which was coupled to L-proline benzyl ester in the presence of EDC and HOBt to give the corresponding dipeptide in 90% yield. Hydrogenolysis of the benzyl ester group of the protected dipeptide using Pd/alumina catalyst produced dipeptide acid 215. Aniline 214 was treated with two equivalents of acid 215 in the presence of 1-propanephosphonic acid cyclic anhydride (T3P). The crude product was recrystallized from ethanol and heptane to give ombitasvir hydrate (XXV). No yields were provided to the final steps of this synthesis.

Enzyme inhibitor

This N-phenylpyrrolidine-based, pan-genotypic HCV NS5A protease inhibitor (FW = 893.14 g/mol), also named ABT-267, targets Nonstructural protein 5A (NS5A), a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication.Ombitasvir exhibits low-picomolar EC50 values against Hepatitis C virus, with superior pharmacokinetics. Although ombitasvir shows a low barrier to resistance, when given as monotherapy, co-administration with other antivirals enhances its barrier to resistance. Indeed, a 12-week, Phase- 3 study demonstrated that a multi-targeted regimen consisting of ombitasvir, dasabuvir and ribavirin is highly effective and showed a low rate of treatment discontinuation.

Drug interactions

Potentially hazardous interactions with other drugs See also ritonavir interactions. Ombitasvir:
Antibacterials: 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.
Diuretics: concentration of furosemide reduced (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).
Oestrogens: avoid with ethinyloestradiol.
Statins: avoid with atorvastatin and simvastatin. Paritaprevir:
Antibacterials: avoid with clarithromycin; concentration possibly reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration reduced by carbamazepine - avoid; possibly reduced by fosphenytoin, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration of both drugs increased with ketoconazole and possibly itraconazole and posaconazole - avoid.
Antivirals: concentration increased by atazanavir; concentration increased by darunavir and concentration of darunavir decreased; avoid with efavirenz, etravirine, indinavir, nevirapine, saquinavir and tipranavir; concentration increased by lopinavir - 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
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration reduced by carbamazepine - avoid; possibly reduced by fosphenytoin, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration of both drugs increased with ketoconazole and possibly itraconazole and posaconazole - avoid.
Antivirals: concentration increased by atazanavir; concentration increased by darunavir and concentration of darunavir decreased; avoid with efavirenz, etravirine, indinavir, nevirapine, saquinavir and tipranavir; concentration increased by lopinavir - 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

Metabolism

Ombitasvir is mainly metabolized by amide hydrolysis followed by CYP2C8-mediated oxidative metabolism .

Metabolism

Ombitasvir is metabolised via amide hydrolysis followed by oxidative metabolism. A total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity.
Paritaprevir is metabolised mainly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200 mg / 100 mg oral dose of 14C paritaprevir / ritonavir to humans, the parent drug was the major circulating component, accounting for approximately 90% of the plasma radioactivity.
At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity.
These metabolites are not expected to have antiviral activity. Ritonavir is extensively metabolised in the liver mainly by cytochrome P450 isoenzymes CYP3A4 and to a lesser extent by CYP2D6. Five metabolites have been identified and the major metabolite has antiviral activity, but concentrations in plasma are low. About 86% of a dose is eliminated through the faeces (both as unchanged drug and as metabolites) and about 11% is excreted in the urine.