Sofosbuvir is a prodrug that is rapidly converted after ingestion to GS-331007, which is efficiently taken up by hepatocytes and converted by cellular kinase to its pharmacologically active uridine analog 5’-triphosphate form GS-461203. The triphosphate is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination.
Sofosbuvir is administered without regard to food; peak plasma concentrations are observed at 0.5–1 hour post-dose. It is 61–65% bound to plasma proteins and is metabolized in the liver. Renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 are 0.4 and 27 hours, respectively. No dose adjustment is required for patients with mild or moderate renal insufficiency, or any degree of hepatic impairment. Sofosbuvir exposure is increased in patients with severe renal impairment, including those on dialysis.
Sofosbuvir is a substrate of drug transporter P-gp; therefore, potent P-gp inducers in the intestine may decrease sofosbuvir concentrations and should not be co-administered.
Sofosbuvir is generally well tolerated. Drug-specific adverse effects are difficult to discern since it is always administered with other antiviral agents. In patients receiving sofosbuvir with ledipasvir, the most commonly reported adverse effects were fatigue, headache, and asthenia. Rare cases of symptomatic bradycardia have been reported patients taking sofosbuvir and amiodarone in combination with another DAAs, particularly in patients also receiving beta blockers, or in those with underlying cardiac comorbidities and/or advanced liver disease.
NS3/4A protease inhibitors are inhibitors of the NS3/4A serine protease, an enzyme involved in post-translational processing and replication of HCV (Figure 49–4).
Capsid C NS3/4A protease inhibitors “ ... previr ” NS5A inhibitors “ ... asvir ” NS5B polymerase inhibitors “ ... buvir ” E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B glycoproteins RNA helicase Cofactors polymerase
FIGURE 49–4 HCV genome and potential targets of drug action. C, E1, E2, etc, protein products of specific genes; Nucs, nucleoside inhibitors; Non-Nucs, nonnucleoside inhibitors. (Adapted, with permission, from Asselah T, Marcellin P: Direct-acting antivirals for the treatment of chronic hepatitis
C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.)
Grazoprevir is a potent, pan-genotypic protease inhibitor, reversibly binding to HCV NS3/4A protease. It is distinct from earlier-generation protease inhibitors due to its pan-genotypic activity, as well activity against some of the major resistance-associated variants (R155K and D168Y) resulting in failure with first-generation protease inhibitors. It is only available in combination with elbasvir for treatment of HCV genotypes 1 and 4.
Grazoprevir can be taken without regard to food. Oral exposures are ~2-fold greater in HCV-infected subjects than in healthy subjects. Peak plasma concentrations are reached at a median of 2 hours after ingestion. Grazoprevir is extensively bound to plasma proteins (98.8%), and distributes predominantly to the liver, likely facilitated by active transport through the OATP1B1/3 liver uptake transporter. It is partially eliminated by oxidative metabolism, primarily by CYP3A and is mostly eliminated in the feces. Its geometric mean terminal half-life is 31 hours.