Influenza Viral Load and Peramivir Kinetics after Single Administration and Proposal of Regimens for Peramivir Administration against Resistant Variants

Abstract

fWe estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (C max ) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage.

Virological response to peramivir treatment in adults hospitalised for influenza-associated lower respiratory tract infections

“…peramivir may serve a useful role [1,7]. Consistent with recent reports, we found an insignificant difference between the two dosing regimens [1,3,7,12], and the most common side effect was gastrointestinal, similar to oseltamivir [1,8].…”

“…Multiple rather than single administration of peramivir has been recommended for patients hospitalised for severe influenza [1,3,7,11,12]. The current data further suggest that for influenzaassociated LRTC (especially with corticosteroid use), because of slower clinical resolution and viral clearance, a treatment duration of >5 days may be necessary.…”

“…However, whether rapid delivery of an i.v. NAI and with repeated dosing can offer a pharmacokinetic advantage in the sickest patients has remained uncertain (especially during the early phase) and warrants further investigation [1,5,11,12]. Practically, in patients with gastrointestinal dysfunction or when oral intake is impossible, i.v.…”

“…subject selection, treatment duration, virology assessment). Correlations of the virological endpoints with clinical resolution as well as peramivir pharmacokinetics/pharmacodynamics in this unique population also warrant evaluation [1,5,12].…”

Quantitative analysis of influenza A (H3N2) E119V and R292K variants in clinical specimens by real-time reverse transcription polymerase chain reaction

“…Viruses were isolated from the samples stored at −80 • C as previously described [25,26]. The susceptibility of isolated viruses and reference viruses, WT (A/Fukui/20/2004), and E119 V (A/Fukui/45/2004) and R292K (A/Kagoshima/2/2012) variants, to NAIs was determined using a NA-XTD chemiluminescence-based NA inhibition assay kit (Life Technologies Corp., Carlsbad, CA, USA) according to the manufacturer's instructions.…”