Velpatasvir

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

Sofosbuvir is an inhibitor of the hepatitis C virus (HCV) NS5B ribonucleic acid (RNA)-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7-2.6 micrometer. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human deoxyribonucleic acid (DNA) and RNA polymerases, nor an inhibitor of mitochondrial RNA polymerase.

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent .

Velpatasvir is a Direct-Acting Antiviral (DAA) 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 . Velpatasvir acts as a defective substrate for NS5A (Non-Structural Protein 5A), a non-enzymatic viral protein that plays a key role in Hepatitis C Virus replication, assembly, and modulation of host immune responses . Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as velpatasvir. Notably, velpatasvir has a significantly higher barrier to resistance than the first generation NS5A inhibitors, such as Ledipasvir and Daclatasvir, making it a highly potent and reliable alternative for treatment of chronic Hepatitis C .

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 Velpatasvir as first line therapy in combination with sofosbuvir for all six genotypes of Hepatitis C . Velpatasvir is currently only available within a fixed dose combination product as Epclusa with Sofosbuvir, another direct acting antiviral. Goals of therapy for Epclusa include 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 and risk of requiring a liver transplant .

Since June 2016, Velpatasvir has been available as a fixed dose combination product with Sofosbuvir, as the commercially available product Epclusa. Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. It is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis and a high barrier to resistance . Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV .

Voxilaprevir is a Direct-Acting Antiviral (DAA) 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 .

Voxilaprevir exerts its antiviral action by reversibly binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) . Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B . By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as voxilaprevir.

Voxilaprevir has been available since July 2017 in a fixed dose combination product with sofosbuvir and velpatasvir as the commercially available product Vosevi. Vosevi is approved for the treatment of adult patients with chronic HCV infection with genotype 1, 2, 3, 4, 5, or 6 infection . Notably, Vosevi is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor . Prior to Vosevi, there were no approved retreatment options for patients who have previously received, and failed, a regimen containing an NS5A inhibitor for treatment of chronic HCV infection.

Velpatasvir
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	Velpatasvir
Generic	Sofosbuvir + velpatasvir + voxilaprevir
Weight	400mg + 100mg + 100mg
Type	Oral tablet
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Sofosbuvir is used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sofosbuvir efficacy has been established in subjects with MCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection.

Velpatasvir is a NS5A inhibitor used to treat chronic hepatitis C infections in patients without cirrhosis or with compensated cirrhosis.

Velpatasvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include therapy with Ribavirin.

When used in combination with Sofosbuvir as the combination product Epclusa, Velpatasvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis .

Voxilaprevir is a nonstructural protein 3 and 4a protease inhibitor used to treat Hepatitis C infections.

Vosevi (Voxilaprevir/Sofosbuvir/Velpatasvir) is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection who have previously been treated with an HCV regimen containing Sofosbuvir without an NS5A inhibitor .

How Velpatasvir works

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator . More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material .

Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202 . NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed . Inhibition of NS5A is also known to produce redistribution of the protein to lipid droplets. The exact role of NS5A in RNA replication is not yet understood although it is known to be an important component.

Voxilaprevir exerts its antiviral action by reversibley binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) . Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B . By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function.

Dosage

Velpatasvir dosage

One 400 mg tablet taken once daily with or without food. Should be used in combination with Ribavirin or in combination with Pegylated Interferon and Ribavirin for the treatment of CHC.

Recommended combination therapy: (HCV Mono-infected and HCV/HIV-1 Co-infected)-

Genotype 1 or 4: Sofosbuvir + Peginterferon alfa + Ribavirin for 12 weeks
Genotype 2: Sofosbuvir + Ribavirin for 12 weeks
Genotype 3: Sofosbuvir + Ribavirin for 24 weeks

Sofosbuvir in combination with Ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are Interferon ineligible

Should be used in combination with Ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation whichever occurs first

A dose recommendation cannot be made for patients with severe renal impairment or end stage renal disease

Side Effects

The most common adverse events observed with Sofosbuvir in combination with ribavirin were fatigue and headache.

The most common adverse events for Sofosbuvir, peginterferon alfa and Ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

The following ADRs occured in <1% of subjects receiving Sofosbuvir in combination regimen.

Hematologic effects: pancytopenia (particularly in subjects receiving concomitant Pegylated Interferon).

Psychiatric disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

Toxicity

Sofosbuvir, as a single agent, has very mild toxicity. The most common adverse reactions are headache and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone .

No indication of carcinogenicity or impairment of fertility/fetal viability .

Precaution

Bradycardia with amiodarone co-administration: Serious symptomatic bradycardia may occur in patients taking amiodarone and Sofosbuvir in combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Co-administration of amiodarone with Sofosbuvir in combination with another DAA is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended.

Interaction

Reduced therapeutic effect with drugs that are potent P-gp inducers in the intestine (eg rifampicin, St. John's wort, carbamazepine & phenytoin), modafinil, phenobarb/ oxcarbazepine, rifabutin/ rifapentine. P-gp &/or BCRP inhibitors. May result in serious symptomatic bradycardia when co-administered with amiodarone in combination with another direct acting antiviral.

Volume of Distribution

The volume of distribution for sofosbuvir has yet to be determined .

1.4-1.6 L/kg .

Elimination Route

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL .

Oral bioavailability of 25-30% .

When provided as the fixed dose combination product Vosevi with Sofosbuvir and Velpatasvir, voxilaprevir reaches a maximum concentration (Cmax) of 192 ng/mL at a maximum time (Tmax) of 4 hours post-dose .

Half Life

Sofosbuvir has a terminal half life of 0.4 hours .

15h .

33 hr

Clearance

The clearance of sofosbuvir has yet to be determined .

Estimated 0.12 L/h/kg [A19175.

Elimination Route

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route .

94% excreted in feces with 77% as parent compound. 0.4% excreted in urine .

Voxilaprevir is primarily eliminated via biliary excretion .

Pregnancy & Breastfeeding use

Pregnancy Category- B. Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective methods of contraception and have monthly pregnancy tests.

Lactation: Unknown if distributed in human breast milk; take into account the importance of therapy to the mother when administered combination with ribavirin and/or peg-interferon alfa; because of the potential for adverse reaction, breastfeeding is not recommended

Contraindication

When Sofosbivur is used in combination with Ribavirin or Peginterferon alfa/ Ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Sofosbuvir combination treatment with Ribavirin or Peginterferon alfa/Ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant, because of the risks for birth defects and fetal death associated with Ribavirin.

Special Warning

Geriatric Use: No dose adjustment of Sofosbuvir is warranted in geriatric patients.

Acute Overdose

The highest dose of Sofosbuvir is a single dose of Sofosbuvir 1200 mg. No specific antidote is available for overdose treatment. Treatment of overdose with Sofosbuvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.