buvir in all genotypes tested. In addition, genotype 2a, 4, and 6 replicons also developed a M289L substitution. Cross resistance is not expected with NS3/4A protease inhibitors, NS5B non-nucleoside inhibitors, or NS5A inhibitors.
Velpatasvir: Velpatasvir prevents hepatitis C viral replication by inhibiting the HCV NS5A protein. Although the exact mechanism is unknown, data suggest NS5A inhibitors may prevent replication by blocking viral hyperphosphorylation. It has been proposed that tight control of phosphorylation versus hyperphosphorylation is needed for efficient viral function.
In cell cultures, all tested genotypes showed reduced susceptibility to velpatasvir, with variants developing amino acid substitutions at NS5A. Combinations of NS5A substitutions often showed greater reductions in susceptibility than single substitutions. Phenotypic analysis showed that single and double combinations of L31V and Y93H/N in genotype 1a, L31V plus Y93H in genotype 1b, Y93H/S in genotype 3a, and L31V and P32A/L/Q/R in genotype 6 conferred greater than 100-fold reduction in velpatasvir susceptibility. In genotype 2a, single mutants F28S and Y93H showed a 91-fold and 46-fold reduced susceptibility to velpatasvir, respectively. The single mutant Y93H conferred a 3-fold reduced susceptibility in genotype 4a. Cross resistance is not expected with NS3/4A protease inhibitors or NS5B non-nucleoside inhibitors. Efficacy has not been established in patients who have previously failed treatment with other regimens that include a NS5A inhibitor.
PHARMACOKINETICS
Sofosbuvir; velpatasvir is administered orally.
Sofosbuvir: After administration, approximately 61% to 65% is bound to plasma protein. In the liver, sofosbuvir is converted from the nucleotide prodrug to the pharmacologically active nucleoside analog triphosphate, GS-461203. This conversion occurs via hydrolysis of the carboxy ester moiety by human cathepsin A (CatA) or carboxylesterase 1 (CES1), phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT 1), and phosphorylation by pyrimidine nucleotide biosynthesis pathway. GS-461203 is then further metabolized by dephosphorylation to form GS-331007, a metabolite that lacks anti-HCV activity and cannot be rephosphorylated. GS-331007 is the predominant circulating metabolite and represents more than 90% of drug related material, while the parent drug accounts for approximately 4%. Elimination occurs primarily through the kidneys with approximately 80% of the dose recovered in the urine (78% as GS-331007, 3.5% as sofosbuvir). Other routes of elimination include the feces (14%) and expired air (2.5%). The median terminal elimination half-life of sofosbuvir and GS-331007 is 0.5 and 25 hours, respectively.
Velpatasvir: After administration, greater than 99.5% is bound to plasma protein. Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4. Biliary excretion accounts for elimination of 77% of the parent drug with 95% of the dose recovered in the feces and 0.4% of the dose recovered in the urine. The median terminal elimination half-life of velpatasvir is 15 hours.
Affected cytochrome P450 isoenzymes and drug transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, OAT2B1, CYP2B6, CYP2C8, CYP3A4
Sofosbuvir and velpatasvir are substrates of the drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In v |
