title: Safety and pharmacokinetics of oseltamivir at standard and high dosages.
abstract: Although clinical evidence is currently lacking, opinion in the literature on avian influenza A/H5N1 suggests that increased doses of the oral neuraminidase inhibitor oseltamivir may offer clinical benefits against highly pathogenic influenza where high levels of viral replication and disseminated infection cause severe disease. We assessed the pharmacokinetics and safety/tolerability of oseltamivir at dosages up to 450 mg twice daily. Healthy adult volunteers were randomised to receive placebo or oseltamivir 75, 225 or 450 mg every 12h for 5 days. Volunteers were followed up to Day 7 for pharmacokinetic parameters, vital signs, adverse events and cardiac safety. In total, 391 volunteers were randomised and evaluated. Pharmacokinetics were linear and dose-proportional, with no evidence of accumulation of oseltamivir or its active metabolite at any dosage. Headache was the most common adverse event (16.8-23.7% across groups), but its incidence was unrelated to dosage. Dosage-related events with oseltamivir included nausea (up to 31.3% of volunteers) and vomiting (up to 16.2%), which generally occurred on Day 1 and lasted <1 day, and possibly dizziness (up to 11.3%). Oseltamivir had no relevant effects on vital signs, laboratory parameters or cardiac function. In conclusion, oseltamivir was well tolerated, with dose-proportional pharmacokinetics and no accumulation. Possible clinical benefit in severe influenza infections could be investigated at dosages higher than those currently recommended.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dutkowski
authors.forename: J R
authors.initials: JR
authors.lastname: Smith
authors.forename: B E
authors.initials: BE
authors.lastname: Davies
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004244:Dizziness / Q000139:chemically induced; D005260:Female; D006261:Headache / Q000139:chemically induced; D006805:Human Experimentation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D053139:Oseltamivir / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D010919:Placebos / Q000008:administration & dosage; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D010919:Placebos; D053139:Oseltamivir