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.
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.
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.
Treatment of chronic hepatitis C infection
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.
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.
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
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.
