Grazoprevir

Grazoprevir Uses, Dosage, Side Effects, Food Interaction and all others data.

Grazoprevir 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 Grazoprevir. Grazoprevir is an inhibitor of NS3/4A, a serine protease enzyme, encoded by HCV genotypes 1 and 4 . These enzymes are essential for viral replication and serve to cleave the virally encoded polyprotein into mature proteins like NS3, NS4A, NS4B, NS5A and NS5B . The barrier for develoment of resistance to NS3/4A inhibitors is lower than that of NS5B inhibitors, another class of DAAs . Subtitutions at amino acid positions 155, 156, or 168 are known to confer resistance. The substitutions of the enzyme's catalytic triad consisting of H58, D82, and S139 are also likely to alter the affinity of the drug for NS3/4A or the activity of the enzyme itself. Despite this disadvantage Grazoprevir is still effective against HCV particularly when paired with Elbasvir.

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 Grazoprevir as first line therapy in combination with Elbasvir for genotypes 1a, 1b, and 4 of Hepatitis C . Grazoprevir and Elbasvir are used with or without 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 .

Grazoprevir is available as a fixed dose combination product with Elbasvir (tradename Zepatier) used for the treatment of chronic Hepatitis C. Approved in January 2016 by the FDA, Zepatier is indicated for the treatment of HCV genotypes 1 and 4 with or without Ribavirin depending on the the presence of resistance associated amino acid substitutions in the NS5A protein and previous treatment failure with Ribavirin, Peginterferon alfa-2a, Peginterferon alfa-2b, or other NS3/4A inhibitors like Boceprevir, Simeprevir, or Telaprevir . When combined together, Grazoprevir and Elbasvir as the combination product Zepatier have been shown to achieve a SVR between 94% and 97% for genotype 1 and 97% and 100% for genotype 4 after 12 weeks of treatment . It can be used in patients with compensated cirrhosis, human immunodeficiency virus co-infection, or severe kidney disease.

Grazoprevir
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Grazoprevir
Generic	Grazoprevir
Grazoprevir Other Names	Grazoprevir
Type
Formula	C₃₈H₅₀N₆O₉S
Weight	Average: 766.903 Monoisotopic: 766.335997918
Protein binding	Grazoprevir is more than 98.8% bound to plasma proteins . It binds both human serum albumin and α1-acid glycoprotein.
Groups	Approved
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Grazoprevir is an antiviral and NS3/4A protease inhibitor used to treat hepatitis C infections.

Grazoprevir is indicated in combination with Elbasvir (as the fixed dose combination product Zepatier) with or without Ribavirin for treatment of chronic HCV genotypes 1a, 1b, or 4 infection in adults.

Grazoprevir is also used to associated treatment for these conditions: Chronic Hepatitis C Genotype 1, Chronic hepatitis C genotype 1a, Chronic hepatitis C genotype 1b, Chronic hepatitis C genotype 3, Chronic hepatitis C genotype 4

How Grazoprevir works

Grazoprevir is a second generation NS3/4a protease inhibitor used to inhibit viral HCV replication. NS3/4a protease is an integral part of viral replication and mediates the cleavage the virally encoded polyprotein to mature proteins (NS3, NS4A, NS4B, NS5A and NS5B) . Grazoprevir inhibits the NS3/4protease enzymes of HCV genotype 1a, 1B, and 4 with IC50 values of 7pM, 4pM, and 62pM, respectively.

Toxicity

The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea .

Food Interaction

Take with or without food.

Volume of Distribution

Grazoprevir has an estimated apparent volume of distribution of 1250 liters . It is thought to distribute primarily to the liver with its uptake facilitated by organic anion transporting polypeptide 1B1/3.

Elimination Route

Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration . Grazoprevir has an absolute bioavailability of 27%. When taken with food the peak concentration of Grazoprevir increases 2.8 fold but this increase in exposure has not been deemed clinically relevant.