A randomized, crossover study to evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination

PLoS One. 2007 Dec 12;2(12):e1305. doi: 10.1371/journal.pone.0001305.


The threat of potential pandemic influenza requires a reevaluation of licensed therapies for the prophylaxis or treatment of avian H5N1 infection that may adapt to man. Among the therapies considered for use in pandemic influenza is the co-administration of ion channel and neuraminidase inhibitors, both to potentially increase efficacy as well as to decrease the emergence of resistant isolates. To better understand the potential for drug interactions, a cross-over, randomized, open-label trial was conducted with amantadine, 100 mg po bid, and oseltamivir, 75 mg po bid, given alone or in combination for 5 days. Each subject (N = 17) served as their own control and was administered each drug alone or in combination, with appropriate wash-out. Co-administration with oseltamivir had no clinically significant effect on the pharmacokinetics (PK) of amantadine [mean ratios (90% CI) for AUC(0-12) 0.93 (0.89, 0.98) and C(max) 0.96 (0.90, 1.02)]. Similarly, amantadine co-administration did not affect oseltamivir PK [AUC(0-12) 0.92 (0.86, 0.99) and C(max) 0.85 (0.73, 0.99)] or the PK of the metabolite, oseltamivir carboxylate [AUC(0-12) 0.98 (0.95, 1.02) and C(max) 0.95 (0.89, 1.01)]. In this small trial there was no evidence of an increase in adverse events. Although many more subjects would need to be studied to rule out a synergistic increase in adverse events, the combination in this small human drug-drug interaction trial appears safe and without pharmacokinetic consequences.

Trial registration: ClinicalTrials.gov NCT00416962.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amantadine / administration & dosage
  • Amantadine / pharmacokinetics*
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics*
  • Area Under Curve
  • Cross-Over Studies
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Middle Aged
  • Oseltamivir / administration & dosage
  • Oseltamivir / pharmacokinetics*


  • Antiviral Agents
  • Oseltamivir
  • Amantadine

Associated data

  • ClinicalTrials.gov/NCT00416962