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

Abstract

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.

Conflict of interest statement

Competing Interests: All of the authors except D. Morrison are employees of the two companies, Roche and Novartis, that jointly financed this study.

Figures

Figure 1. Plasma amantadine concentrations (mean values±standard deviation) following administration of 100-mg BID amantadine for five days (open circles) or 100 mg BID amantadine plus 75 mg BID oseltamivir (open squares) in 17 healthy volunteers

Figure 2. Plasma oseltamivir concentrations (mean values±standard deviation) following administration of 100-mg BID amantadine for five days (open circles) or 100 mg BID amantadine plus 75 mg BID oseltamivir (open squares) in 17 healthy volunteers

Figure 3. Plasma oseltamivir carboxylate concentrations (mean values±standard deviation) following administration of 75-mg BID oseltamivir for five days (open circles) or 75 mg BID oseltamivir plus 100 mg BID amantadine (open squares) in 17 healthy volunteers