Velpatasvir is administered without regard to food; peak plasma concentrations are observed at 3 hours post-dose. It is >99% bound to plasma proteins. Metabolism is by CYP2B6 CYP2C8, and CYP3A4. Its median terminal half-lives is 15 hours.
Velpatasvir and sofosbuvir are substrates of P-gp and BCRP; velpatasvir is also transported by OATP1B1 and OATP1B3. Inducers of P-gp and/or moderate or potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease plasma concentrations of velpatasvir and/or sofosbuvir; co-administration with drugs that inhibit P-gp and/ or BCRP may increase velpatasvir and/or sofosbuvir concentrations and drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir.
The most common adverse events in patients receiving velpatasvir/sofosbuvir were headache and fatigue.
NS5B is an RNA-dependent RNA polymerase involved in post-translational processing that is necessary for replication of HCV. The enzyme has a catalytic site for nucleoside binding and at least four other sites at which a non-nucleoside compound can bind and cause allosteric alteration. The enzyme’s structure is highly conserved across all HCV genotypes, giving agents that inhibit NS5B efficacy against all six genotypes.
There are two classes of polymerase inhibitors; these act at distinct stages of RNA synthesis. Nucleoside/nucleotide analogs (eg, sofosbuvir) target the catalytic site of NS5B, and are activated within the hepatocyte through phosphorylation to nucleoside triphosphate, which competes with nucleotides, resulting in chain termination. Non-nucleoside analogues (e.g., dasabuvir) act as allosteric inhibitors of NS5B.
Dasabuvir is a non-nucleoside NS5B polymerase inhibitor, available only as a fixed-dose combination with ombitasvir, paritaprevir, and ritonavir for treatment of HCV genotype 1. Ritonavir functions as a pharmacologic booster to increase paritaprevir plasma concentrations.
The absolute bioavailability of dasabuvir is 70%. Peak plasma concentrations are reached 4 hours post-ingestion of the combination. It is >99.5% protein-bound. The primary route of metabolism is via CYP2C8, as well as CYP3A. This combination is contraindicated in patients with moderate or severe hepatic impairment.
The metabolism of paritaprevir, ritonavir, and dasabuvir by the CYP3A system incurs multiple potential drug-drug interactions. Co-administration of the combination with drugs that highly dependent on CYP3A for clearance, moderate or strong inducers of CYP3A, strong inducers of CYP2C8, or strong inhibitors of CYP2C8 is contraindicated.
The most commonly reported adverse reactions in patients receiving dasabuvir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol-containing contraceptive medications.
The nucleotide analog sofosbuvir is administered in combination with several other anti-HCV medications, including daclatasvir, simeprevir, peginterferon-alfa plus ribavirin, or ribavirin alone. It is also available in a fixed-dose combination with ledipasvir for treatment of HCV genotypes 1, 4, 5, and 6 (see Table 49–7).