Ledipasvir was the first NS5A inhibitor to be available in the United States. It is available in a fixed-dose combination with sofosbuvir. Ledipasvir is not recommended for treatment of HCV genotype 2 infection (since potency is lost in the presence of the highly prevalent L31M polymorphism) or genotype 3 (due to the availability of more efficacious therapies (see Table 49–7).
Ledipasvir is not affected by food intake. Median peak plasma concentrations occur 4–4.5 hours after oral administration of ledipasvir/sofosbuvir. It is highly bound (>99.8%) to plasma proteins; unchanged ledipasvir is the major species present in feces. The median terminal half-life of ledipasvir following administration of ledipasvir/sofosbuvir is 47 hours. No dose adjustment is required in the setting of mild or moderate renal insufficiency or mild, moderate or severe hepatic insufficiency. The dose in patients with severe renal insufficiency has not yet been determined.
Ledipasvir is an inhibitor of the drug transporters P-gp and BCRP and may increase intestinal absorption of co-administered substrates for these transporters. Additionally, co-administration of P-gp inducers (e.g., rifampin or St. John’s wort) with ledipasvir/ sofosbuvir may decrease plasma concentrations of both of these agents.
The most common adverse reactions in patients receiving ledipasvir/sofosbuvir were fatigue, headache and asthenia. Serious symptomatic bradycardia has been reported in patients receiving ledipasvir with sofosbuvir and amiodarone.
Ombitasvir is available only as a fixed-dose combination with paritaprevir and ritonavir for the treatment of HCV genotype 4, and is given in combination with dasabuvir, paritaprevir, and ritonavir to treat genotype 1 (see Table 49–7). As in HIV infection, ritonavir is administered as a pharmacologic “booster” to increase plasma concentrations of paritaprevir via its effect on CYP3A, although it does not have activity against HCV.
The absolute bioavailability of ombitasvir is 48%. Peak plasma concentrations are reached 5 hours post-ingestion of the combination. It is 99.9% protein-bound; the route of metabolism is via biliary excretion. Ombitasvir/paritaprevir/ritonavir is contraindicated in patients with moderate or severe hepatic impairment.
Ombitasvir is an inhibitor of UGT1A1. Although ombitasvir is not metabolized by the CYP3A system, paritaprevir, ritonavir, and dasabuvir are, with the resulting potential for multiple 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 ombitasvir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol-containing contraceptive medications.
Velpatasvir is available only in a fixed-dose combination with the sofosbuvir. It is the first once-daily single-tablet regimen with pangenotypic activity. 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.