title: High and continuous exposure of laninamivir, an anti-influenza drug, may work suppressively to generate low-susceptibility mutants in animals.
abstract: Laninamivir octanoate (Inavir(®); Daiichi Sankyo, Tokyo, Japan) is an anti-influenza drug that provides complete treatment by a single inhalation. It works as a long-acting neuraminidase (NA) inhibitor by means of high and continuous exposure of laninamivir, its active metabolite, in the lungs of mice after intranasal administration. Even after 6 days after intranasal administration of 236 μg/kg laninamivir octanoate, the concentration of laninamivir in the lungs was maintained more than 2-3 orders higher than 50% inhibitory concentrations of laninamivir to N1 NAs, about 2 orders higher than N2 NA of seasonal influenza A viruses, and more than about 50 times higher than influenza B virus NA. From A/H1N1 influenza virus-infected and laninamivir octanoate-treated mice, no low-susceptibility mutants to laninamivir were obtained. In contrast, four different mutants to oseltamivir were obtained from mice administered oseltamivir phosphate, which required repeated administration for treatment under the experimental condition, showing similar virus load reduction between both compounds. This finding suggested the unique characteristics of laninamivir octanoate in mice may work suppressively to generate low-susceptibility mutants.
authors: Biological Research Laboratories, Daiichi Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo, Japan.
authors: Shuku
authors: S
authors: Kubo
authors: Akane
authors: A
authors: Tokumitsu
authors: Takanori
authors: T
authors: Tomozawa
authors: Masayo
authors: M
authors: Kakuta
authors: Makoto
authors: M
authors: Yamashita
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral; D005260:Female; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics*; D020128:Inhibitory Concentration 50; D008168:Lung / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000187:drug effects*; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology; D011714:Pyrans; D012794:Sialic Acids; D019562:Viral Load; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D053139:Oseltamivir; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir