title: Combination therapy with amantadine, oseltamivir and ribavirin for influenza A infection: safety and pharmacokinetics.
abstract: BACKGROUND
  Antiviral resistance among influenza A viruses is associated with high morbidity and mortality in immunocompromised hosts. However, treatment strategies for drug-resistant influenza A are not established. A triple-combination antiviral drug (TCAD) regimen consisting of amantadine (AMT), oseltamivir (OSL) and ribavirin (RBV) demonstrated good efficacy in an animal model.
  
  
  METHODS
  We first analysed the pharmacokinetics (PKs) of TCAD therapy in healthy volunteers. We then performed a pilot study of TCAD therapy in patients undergoing chemotherapy or haematopoietic cell transplantation. AMT (75 mg), OSL (50 mg) and RBV (200 mg) were administered three times a day for 10 days. The safety and PKs of TCAD therapy were monitored.
  
  
  RESULTS
  The PKs of TCAD therapy in healthy volunteers was shown to be similar to the PKs of each drug individually from a single dose. In the pilot study, six immunocompromised patients received TCAD therapy and one patient received OSL monotherapy. All but one patient completed 10 days of TCAD therapy without side effects; one patient receiving TCAD was withdrawn from the study because of respiratory failure and ultimately recovered. Viral load was decreased after TCAD therapy, despite the presence of either AMT- or OSL-resistant virus in two cases. One patient with 2009 influenza A/H1N1 receiving OSL monotherapy developed confirmed OSL resistance during treatment.
  
  
  CONCLUSIONS
  TCAD therapy had similar PKs to each individual antiviral during monotherapy following a single dose and can be administered safely in immunocompromised patients.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Seo
authors.forename: Janet A
authors.initials: JA
authors.lastname: Englund
authors.forename: Jack T
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Paul A
authors.initials: PA
authors.lastname: Tambyah
authors.forename: Christian
authors.initials: C
authors.lastname: Renaud
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Went
authors.forename: Menno D
authors.initials: MD
authors.lastname: de Jong
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boeckh
mesh_terms: D000328:Adult; D000547:Amantadine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D009980:Influenza A virus / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008297:Male; D009154:Mutation; D053139:Oseltamivir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010865:Pilot Projects; D012254:Ribavirin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019562:Viral Load; D055815:Young Adult
chemical_list: D053139:Oseltamivir; D012254:Ribavirin; D000547:Amantadine