sofosbuvir, velpatasvir and voxilaprevir

Action and Spectrum

Actions and spectrum: 

• sofosbuvir: an analog nucleotide inhibitor of the HCV non-structural protein (NS)5B polymerase, which is required for viral replication. 
• velpatasvir: an inhibitor of the HCV NS5A protein, which is also required for viral replication. 
• voxilaprevir: is an inhibitor of the HCV NS3/4A protease required for viral replication and assembly. 

Combining these three drugs provides a potent and highly effective treatment option for patients with chronic HCV infection. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Nausea (10-13%) 

Diarrhea (13-14%) 

Fatigue (17-19%) 

Headache (21-23%)  

1-10% 

Insomnia (3-6%) 

Asthenia (4-6%)  

Post marketing Reports 

Cardiac disorders: bradycardia 

Skin and subcutaneous tissue: angioedema, Rashes, swelling 

Black Box Warning

Black Box Warning:  

There is no black box warning for the combination of sofosbuvir, velpatasvir, and voxilaprevir. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Patients with hypersensitivity reactions to sofosbuvir, velpatasvir, or voxilaprevir. 
• Patients taking specific strong CYP3A inducers can decrease the effectiveness of sofosbuvir, velpatasvir, and voxilaprevir. 
• Patients with hepatic impairment, as the safety and efficacy of this combination, have not been established in this population. 
• Patients with moderate or severe renal impairment, as the safety and efficacy of this combination, have not been established in this population. 
• Patients with advanced cirrhosis with a Model for End-Stage Liver Disease (MELD) score greater than or equal to 12, as the safety and efficacy of this combination have not been established in this population.

Caution: 

The combination of sofosbuvir, velpatasvir, and voxilaprevir is generally well-tolerated, but some cautions should be considered. One caution is in patients with hepatic impairment, as the combination has not been studied in this population.

Additionally, the combination should be used with caution in patients with hepatitis B infection, as reactivation of the hepatitis B virus can occur during treatment.  

Comorbidities: 

sofosbuvir, velpatasvir, and voxilaprevir are medications used to treat chronic hepatitis C (HCV) infections. Patients with chronic HCV infection often have comorbidities such as liver cirrhosis, HIV coinfection, renal impairment, and cardiovascular disease. These comorbidities may affect the choice of therapy and dosage of the medication.

For example, patients with liver cirrhosis may require lower doses of sofosbuvir, velpatasvir, and voxilaprevir due to impaired liver function. Patients with HIV coinfection may require close monitoring of drug interactions between HCV medications and antiretroviral therapy.

Patients with renal impairment may require dose adjustments or close monitoring of renal function during treatment. Patients with cardiovascular disease may require close monitoring of cardiac function during treatment, as some HCV medications may affect heart function. 

Pregnancy / Lactation

Pregnancy consideration: pregnancy category B 

Lactation: safety and efficacy not established  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

• sofosbuvir, velpatasvir, and voxilaprevir are antiviral medications used to treat chronic hepatitis C virus. 
• sofosbuvir is a prodrug converted to an active metabolite that inhibits the HCV NS5B RNA-dependent RNA polymerase, preventing HCV replication. Velpatasvir is an HCV NS5A inhibitor that prevents HCV assembly and release. voxilaprevir is an HCV NS3/4A protease inhibitor that prevents cleavage of the HCV polyprotein, thereby inhibiting HCV replication. 
• Combining these three drugs results in a high sustained virologic response rate in patients with chronic HCV infection, including those with genotypes 1, 2, 3, 4, 5, or 6.  

Pharmacodynamics: 

• sofosbuvir, velpatasvir, and voxilaprevir are antiviral drugs used in combination to treat chronic hepatitis C virus (HCV) infections. 
• Sofosbuvir is an analog nucleotide inhibitor of the HCV nonstructural protein (NS)5B RNA-dependent RNA polymerase. It works by interfering with the replication process of the virus, thus preventing it from multiplying and causing further damage. 
• velpatasvir is a pan-genotypic inhibitor of HCV NS5A, a viral protein that plays a vital role in the replication and assembly of new virus particles. By inhibiting NS5A, velpatasvir prevents the virus from replicating and spreading. 
• voxilaprevir is a protease inhibitor that blocks the activity of the HCV NS3/4A protease enzyme, which is essential for viral replication. By inhibiting this enzyme, voxilaprevir prevents the virus from replicating and spreading. 

The combination of sofosbuvir, velpatasvir, and voxilaprevir provides a potent antiviral effect against HCV, targeting different stages of the virus replication cycle. The combination is effective against all genotypes of HCV and is used for the treatment of chronic HCV infection in adults who have failed previous treatment with direct-acting antiviral therapy.  

Pharmacokinetics: 

Absorption 

The combination is well absorbed orally, with peak plasma concentrations achieved within 1-4 hours after administration.  

Distribution 

sofosbuvir, velpatasvir, and voxilaprevir are highly protein-bound, with binding ranging from 61% to 94%. The volume of distribution of sofosbuvir, velpatasvir, and voxilaprevir is approximately 0.6, 47, and 125 L, respectively.  

Metabolism 

sofosbuvir is metabolized in the liver to its active metabolite, GS-461203, by hydrolysis and is eliminated primarily through the kidneys. Velpatasvir is mainly metabolized by the liver, primarily by CYP2B6 and CYP3A4, and is eliminated in the feces and urine. Voxilaprevir is primarily metabolized by CYP3A4 and is eliminated mainly in feces.  

Elimination and excretion 

sofosbuvir and its metabolites are primarily eliminated through the kidneys, with approximately 80% of the administered dose excreted in the urine. Velpatasvir is mainly eliminated in the feces (74%) and urine (17%). Voxilaprevir is eliminated primarily in the feces (91%) and urine (3%). 

Adminstartion

Administration: 

sofosbuvir, velpatasvir, and voxilaprevir are administered orally, usually as a fixed-dose combination tablet. The recommended dose is one tablet once daily with food.

The treatment duration varies depending on the patient’s genotype, treatment history, and liver function but generally ranges from 8 to 12 weeks.

Patient Information Leaflet

Patient information leaflet 

Generic Name: sofosbuvir, velpatasvir and voxilaprevir 

Pronounced: [ soe-fos-bue-vir, vel-pat-as-vir, and-vox-i-la-pre-vir ]  

Why do we use sofosbuvir, velpatasvir and voxilaprevir? 

The use of sofosbuvir, velpatasvir, and voxilaprevir combination during lactation is not recommended. It is unknown whether the combination’s components are excreted in human milk, and there is a potential for severe adverse reactions in nursing infants.

Breastfeeding women who require treatment with this medication should consult with their healthcare provider to discuss the potential risks and benefits. Alternatives should be considered, and the decision to breastfeed should be made after carefully considering the risks and benefits for both the mother and the infant.