title: Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment.
abstract: OBJECTIVE
  Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B.
  
  
  METHODS
  288 susceptible, healthy volunteers (ages 18-45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials.
  
  
  METHODS
  For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100-800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50-800 mg/day.
  
  
  RESULTS
  The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery.
  
  
  RESULTS
  In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected.
  
  
  CONCLUSIONS
  Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.
authors.affiliation: Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Barroso
authors.forename: John
authors.initials: J
authors.lastname: Treanor
authors.forename: Larisa
authors.initials: L
authors.lastname: Gubareva
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hayden
mesh_terms: D000146:Acids, Carbocyclic; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D003517:Cyclopentanes / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006146:Guanidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D006261:Headache / Q000139:chemically induced; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000302:isolation & purification; D009981:Influenza B virus / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy* / Q000517:prevention & control* / Q000821:virology; D008875:Middle Aged; D017817:Nasal Lavage Fluid / Q000821:virology; D009325:Nausea / Q000139:chemically induced; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000146:Acids, Carbocyclic; D003517:Cyclopentanes; D006146:Guanidines; D009439:Neuraminidase; C414210:peramivir