ABSTRACT
Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89-1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction.
Subject(s)
2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics , Antiviral Agents/pharmacokinetics , Benzofurans/pharmacokinetics , Famotidine/pharmacokinetics , Hepacivirus/drug effects , Imidazoles/pharmacokinetics , Quinoxalines/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles/adverse effects , 2-Pyridinylmethylsulfinylbenzimidazoles/pharmacology , Adult , Amides , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Benzofurans/adverse effects , Benzofurans/blood , Benzofurans/pharmacology , Carbamates , Cyclopropanes , Demography , Drug Interactions , Famotidine/adverse effects , Famotidine/pharmacology , Female , Humans , Imidazoles/adverse effects , Imidazoles/blood , Imidazoles/pharmacology , Male , Middle Aged , Pantoprazole , Quinoxalines/adverse effects , Quinoxalines/blood , Quinoxalines/pharmacology , Sulfonamides , Time Factors , Young AdultABSTRACT
The A9L open reading frame of vaccinia virus was predicted to encode a membrane-associated protein. A transcriptional analysis of the A9L gene indicated that it was expressed at late times in vaccinia virus-infected cells. Late expression, as well as virion membrane association, was demonstrated by the construction and use of a recombinant vaccinia virus encoding an A9L protein with a C-terminal epitope tag. Immunoelectron microscopy revealed that the A9L protein was associated with both immature and mature virus particles and was oriented in the membrane with its C terminus exposed on the virion surface. To determine whether the A9L protein functions in viral assembly or infectivity, we made a conditional-lethal inducible recombinant vaccinia virus. In the absence of inducer, A9L expression and virus replication were undetectable. Under nonpermissive conditions, viral late protein synthesis occurred, but maturational proteolytic processing was inhibited, and there was an accumulation of membrane-coated electron-dense bodies, crescents, and immature virus particles, many of which appeared abnormal. We concluded that the product of the A9L gene is a viral membrane-associated protein and functions at an early stage in virion morphogenesis.
