Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Abstract

The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM one hour after lethal challenge with 5 MLD 50 of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by 7 daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24 hours after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

Widespread use of neuraminidase inhibitors in Japan

“…Peramivir exhibits strong neuraminidase inhibitory activity against influenza A and B viruses [17], including pandemic H1N1 2009 and highly pathogenic viruses, such as the H5N1 subtype [18,19]. The most important characteristics of peramivir are the certainty of drug delivery because it is administered intravenously and its long-lasting antiviral activity.…”

Quantification of peramivir (a novel anti-influenza drug) in human plasma by hydrophilic interaction chromatography/tandem mass spectrometry

“…Peramivir, generated by using the structure-based drug design, has three chemical groups that interact with active-site residues of the influenza virus neuraminidase protein, resulting in the tight binding and a slow rate of dissociation [4,5]. Therefore, peramivir offers the advantage of a markedly longer half-life of binding to the neuraminidase active site, permitting less frequent dosing [6].…”

Efficacy of Repeated Intravenous Administration of Peramivir against Highly Pathogenic Avian Influenza A (H5N1) Virus in Cynomolgus Macaques

“…Animal studies with mice and ferrets showed that repeated intramuscular injections of peramivir were effective against infection with HPAIV A/Vietnam/ 1203/04 (H5N1) (7,23). Although mouse and ferret models have provided insight into the pathogenesis of H5N1 HPAIV in mammalian hosts, the pathogenicity in those models cannot be directly extrapolated to humans.…”

“…In vitro and in vivo studies have demonstrated that H5N1 HPAIVs were sensitive to NA inhibitors, including oseltamivir, zanamivir, laninamivir, and peramivir (7)(8)(9). Of these, oseltamivir has been the most widely used and was demonstrated to improve the survival of patients, although oseltamivir-resistant H5N1 HPAIVs with mutations at positions H275Y and N295S (N1 numbering) of the NA were isolated from patients during antiviral treatment (10).…”