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 12 h 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