Hepcinat (Sofosbuvir) 400 mg 28 tab., NATCO, India

Interchangeable drugs with the same active ingredient:

Grateziano

Sovaldi

Harvoni

compound

active ingredient : sofosbuvir;

1 coated tablet contains 400 mg sofosbuvir;

excipients : mannitol (E 421), microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate

tablet shell: polyvinyl alcohol, titanium dioxide, macrogol, talc.

Dosage form

Film-coated tablets.

Basic physical and chemical properties: white capsule-shaped tablets, film-coated, engraved with "GSI" on one side and "7977" on the other.

Pharmacological group

Antivirals of direct action.

ATX code J05A X15.

Pharmacological properties

Pharmacological

mechanism of action

Sofosbuvir is a pangenotypic inhibitor of the hepatitis C virus NS5B RNA polymerase, which is important for viral replication. Sofosbuvir is a nucleotide depot form that, after participating in intracellular metabolism, forms a pharmacologically active uridine analog triphosphate (GS-461203), which can be introduced into the RNA of the hepatitis C virus by NS5B polymerase, and acts as a chain termination agent. In a biochemical assay, GS-461203 inhibited the polymerase activity of NS5B recombinants in hepatitis C virus genotypes 1b, 2a, 3a, and 4a with 50% inhibitory concentration (IC 50 ) values ranging from 0.7 to 2.6 µm. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerase, nor is it an inhibitor of mitochondrial RNA polymerase.

antiviral action

In HCV replication assays, the effective concentration (EC 50 ) values of sufosbuvir against full-length REPLIKON genotypes 1a, 1b, 2a, 3a, and 4a were 0.04, 0.11, 0.05, 0.05, and 0.04 µm, respectively, and the values The EC50 of sofosbuvir against hybrid REPLIKON 1b encoding NS5B genotype 2b, 5a or 6a ranged from 0.014 to 0.015 µm. Mean ± SD EC 50 of sofosbuvir against REPLIKON hybrids encoding NS5B sequences from clinical strains was 0.068 ± 0.024 μm for genotype 1a (n = 67), 0.11 ± 0.029 μm for genotype 1b (n = 29), 0.035 ± 0.018 μm for genotype 2 (n = 15) and 0.085 ± 0.034 µm for genotype 3a (n = 106). In these assays, the in vitro antiviral activity of sofosbuvir against the less common genotypes 4, 5 and 6 was similar to that observed for genotypes 1, 2 and 3.

The presence of 40% human serum did not affect the antiviral effect of sofosbuvir on HCV.

stability

Cell culture. Replicon HCV with reduced sensitivity to sofosbuvir has been selected in cell culture for many genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Decreased susceptibility to sofosbuvir was associated with the primary NS5B S282T substitution in all genotypes of the REPLIKON assay. Targeted S282T substitution mutagenesis in REPLIKON 8 genotypes provided a 2-18-fold reduction in sensitivity to sofosbuvir and an 89-99% reduction in the possibility of viral replication compared to the corresponding wild type. In biochemical analyzes, the recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a, which expresses the S282T substitution, showed reduced sensitivity to GS-461203 compared to the corresponding wild types.

Clinical researches. In a pooled analysis of 991 patients who were taking sofosbuvir in the phase 3 study, 226 patients were selected for the analysis of persistence of virological failure and early discontinuation of the drug, they should have an RNACV > 1000 IU/mL. After initial NS5B sequences were available for 225 of 226 patients with deep sequencing data (analysis dropout 1%) from 221 of these patients. The S282T substitution associated with sofosbuvir resistance was not detected in any of these patients by deep sequencing or population sequencing. The S282T substitution in NS5B was found in one patient who received Sovaldi monotherapy in a phase 2 study. This patient had <1% HCV S282T at baseline and S282T (>99%) at week 4 post-treatment, resulting in a 13.5-fold change in sofosbuvir EC 50 and reduced the possibility of viral replication. The S282T substitution returned to wild type over the next 8 weeks and was no longer detected by deep sequencing at week 12 post-treatment.

Two NS5B substitutions, L159F and V321A, were found in multiple genotype post-treatment repeat samples from 3 patients infected with HCV in phase 3 clinical trials. No change in phenotypic susceptibility to sofosbuvir or ribavirin was found in isolated patients with these substitutions. In addition, S282R and L320 substitutions were detected during deep sequencing treatment in a pre-transplant patient with a partial response to treatment. The clinical significance of these findings is unknown.

Impact of HCV Outbound Polymorphisms on Treatment Outcome

Outlet NS5B sequences were generated for 1292 patients in the phase 3 study by population sequencing, and no S282T substitution was found in any patient with the original sequence. When evaluating the analysis of the influence of baseline polymorphisms on the result of the assessment, no statistically significant relationship was found between the presence of the NS5B HCV variant at the beginning and after treatment.

cross resistance

HCV replicons that express the S282T substitution associated with sofosbuvir resistance were fully sensitive to other classes of HCV antiviral agents. Sofosbuvir retained activity against the NS5B, L159F and L320F substitutions associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of action, such as non-nucleoside NS5B inhibitors, NS3 protease inhibitors, and NS5A inhibitors.

Pharmacokinetics

Sofosbuvir is a nucleotide depot form that is intensively involved in metabolism. The active metabolite is formed in hepatocytes and is not found in plasma. The main (>90%) metabolite GS-331007 is inactive. It is formed by sequential and parallel pathways leading to the formation of an active metabolite.

absorption

The pharmacokinetic properties of sofosbuvir and the main circulating metabolite GS-331007 were evaluated in healthy adult patients and patients with chronic hepatitis C. After administration, sofosbuvir was rapidly absorbed, and the highest plasma concentration was found ~ 0.5-2 h after dosing, regardless of its level. . The highest plasma concentration of GS-331007 was found 2-4 hours post-dose. Based on population pharmacokinetic analysis in patients with genotypes 1-6 HCV infection (n = 986), steady-state AUC 0-24 for sofosbuvir and GS-331007 was 1010 ng h/mL and 7200 ng h/mL, respectively. In healthy patients (n = 284), sofosbuvir and GS-331007 AUC 0-24 were 57% higher and 39% lower, respectively, than in patients infected with HCV.

The influence of food. Under dietary conditions, taking a single dose of sofosbuvir with a normal, high-fat meal slowed the absorption rate of sofosbuvir. The volume of absorption of sofosbuvir was increased by approximately 1.8 times with little effect on maximum concentration. The action of GS-331007 did not change with a high-fat meal.

Spread

Sofosbuvir is not