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


BACKGROUND
ClinicalTrials.gov NCT00416962.
Morrison
Dennis
D
Bio-Kinetic Clinical Applications, Springfield, Missouri, United States of America.
Roy
Sandip
S
Rayner
Craig
C
Amer
Ahmed
A
Howard
Dan
D
Smith
James R
JR
Evans
Thomas G
TG
D000293:Adolescent; D000328:Adult; D000547:Amantadine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053139:Oseltamivir / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D053139:Oseltamivir; D000547:Amantadine