Elbasvir/grazoprevir should not be administered to patients with moderate or severe hepatic impairment, or in conjunction with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz.
The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur.
Paritaprevir is only available as a fixed-dose combination with ombitasvir and ritonavir for treatment of HCV genotype 4, and is administered in combination with dasabuvir for genotype 1 infection. Ritonavir functions as a pharmacologic booster of paritaprevir concentrations via its effect on CYP metabolism, although it does not have activity against HCV.
The absolute bioavailability of paritaprevir is 53%. Peak plasma concentrations are reached 4–5 hours post-ingestion of the combination. It is ~98% protein-bound. The primary route of metabolism is via CYP3A4, as well as CYP3A5. Ombitasvir/ paritaprevir/ritonavir 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 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 paritaprevir were nausea, pruritus and insomnia. Increased serum aminotransferases have also been reported, particularly in women using concomitant ethinyl estradiol–containing contraceptive medications.
Simeprevir was one of the earliest protease inhibitors available; however, it is considered a second-generation HCV protease inhibitor because of the enhanced binding affinity and specificity for NS3/4A. It is used in combination with sofosbuvir, with or without ribavirin, for treatment of HCV genotype 1, or it may be administered in combination with peg interferon-alfa and ribavirin. Simeprevir must be taken with food to maximize absorption. Mean absolute bioavailability is 62%. Peak plasma concentrations are reached 4–6 hours post-ingestion. It is extensively bound to plasma proteins (>99%), metabolized in the liver by CYP3A pathways, and undergoes biliary excretion. Simeprevir is not recommended in patients with moderate or severe hepatic impairment because of 2to 5-fold increases in exposure. In addition, mean simeprevir exposures are more than threefold higher in patients of East Asian ancestry compared with Caucasians, leading to potentially higher frequencies of adverse events.
Simeprevir is a substrate and mild inhibitor of CYP3A and a substrate and inhibitor of P-gp and OATP1B1/3. Co-administration with moderate or strong inhibitors or inducers of CYP3A may significantly increase or decrease the plasma concentration of simeprevir.
In patients with genotype 1a, the presence of a baseline NS3A polymorphism Q80K was associated with significantly reduced SVR at 12 weeks in patients treated with simeprevir plus peginterferon and ribavirin. Therefore, baseline screening for the Q80K mutation is recommended prior to initiation of therapy.