MK-5172: a second-generation protease inhibitor for the treatment of hepatitis C virus infection

Abstract

The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 - 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.

Elbasvir/Grazoprevir

“…1,15,16 Grazoprevir binds to the serine NS3/4A protease responsible for cleaving the HCV polyprotein into the proteins that enable HCV RNA replication and virion assembly. 1,14 Elbasvir is effective against HCV genotypes 1 and 4 at picomolar and lower levels. 1 In vitro studies show that grazoprevir is effective against HCV genotypes 1, 2, 3, and 4 at nanomolar and lower levels.…”

“…1 Steady-state levels for elbasvir/grazoprevir are reached within about 6 days, with a half-life of 24 hours for elbasvir and 31 hours for grazoprevir. 1,14 Population pharmacokinetic analyses indicate that the AUC of elbasvir and grazoprevir will be increased by 16% and 45%, respectively, in patients 65 years or older compared with patients younger than 65 years of age; increased by 50% and 30%, respectively, in female patients compared with male patients; and increased by 15% and 50%, respectively, in Asian patients compared with White patients. 1 Population pharmacokinetic analyses indicate that the pharmacokinetics of elbasvir and grazoprevir are not clinically altered by weight or renal impairment.…”

“…Coadministration of grazoprevir with efavirenz can decrease grazoprevir levels, whereas coadministration with ritonavir-boosted lopinavir, atazanavir, or darunavir can increase grazoprevir levels. 14,40,41 Grazoprevir may modestly increase ritonavir-boosted atazanavir levels. 14,40 Any dosage adjustments of concomitant medications made at the time of initiation of elbasvir/grazoprevir therapy should be readjusted at the time of completion of elbasvir/grazoprevir therapy.…”

“…14,40,41 Grazoprevir may modestly increase ritonavir-boosted atazanavir levels. 14,40 Any dosage adjustments of concomitant medications made at the time of initiation of elbasvir/grazoprevir therapy should be readjusted at the time of completion of elbasvir/grazoprevir therapy. The pharmacokinetic parameters of sofosbuvir or its metabolite GS-331007 were minimally affected by coadministration with elbasvir/grazoprevir.…”

“…15 Pharmacokinetic parameters are not altered when grazoprevir is administered with pitavastatin, methadone, buprenorphine, or naloxone; however, grazoprevir can increase atorvastatin levels by 5.7-fold. 14,42,43 Coadministration with midazolam does not affect grazoprevir levels, but midazolam levels can be increased by 30%. Rifampin can cause increased grazoprevir levels.…”