title: Combinations of oseltamivir and peramivir for the treatment of influenza A (H1N1) virus infections in cell culture and in mice.
abstract: Oseltamivir and peramivir are being considered for combination treatment of serious influenza virus infections in humans. Both compounds are influenza virus neuraminidase inhibitors, and since peramivir binds tighter to the enzyme than oseltamivir carboxylate (the active form of oseltamivir), the possibility exists that antagonistic interactions might result when using the two compounds together. To study this possibility, combination chemotherapy experiments were conducted in vitro and in mice infected with influenza A/NWS/33 (H1N1) virus. Treatment of infected MDCK cells was performed with combinations of oseltamivir carboxylate and peramivir at 0.32-100μM for 3 days, followed by virus yield determinations. Additive drug interactions with a narrow region of synergy were found using the MacSynergy method. In a viral neuraminidase assay with combinations of inhibitors at 0.01-10nM, no significant antagonistic or synergistic interactions were observed across the range of concentrations. Infected mice were treated twice daily for 5 days starting 2h prior to virus challenge using drug doses of 0.05-0.4mg/kg/day. Consistent and statistically significant increases in the numbers of survivors were seen when twice daily oral oseltamivir (0.4mg/kg/day) was combined with twice daily intramuscular peramivir (0.1 and 0.2mg/kg/day) compared to single drug treatments. The data demonstrate that combinations of oseltamivir and peramivir perform better than suboptimal doses of each compound alone to treat influenza infections in mice. Treatment with these two compounds should be considered as an option.
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, United States. don.smee@usu.edu
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Brett L
authors.initials: BL
authors.lastname: Hurst
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Wong
authors.forename: E Bart
authors.initials: EB
authors.lastname: Tarbet
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D003517:Cyclopentanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D053139:Oseltamivir; D009439:Neuraminidase; C414210:peramivir