laninamivir and Disease-Models--Animal

Oseltamivir and zanamivir are currently licensed worldwide for influenza treatment and chemoprophylaxis. Both drugs require twice-daily administration for 5 days for treatment. A new influenza drug, laninamivir (code name R-125489), and its prodrug form, CS-8958 (laninamivir octanoate or laninamivir prodrug), which are long-acting neuraminidase inhibitors, are introduced in this review. Laninamivir potently inhibited the neuraminidase activities of various influenza A and B viruses, including subtypes N1-N9, pandemic (2009) H1N1 virus, highly pathogenic avian influenza (HPAI) H5N1 viruses and oseltamivir-resistant viruses. Because of the long retention of laninamivir in mouse lungs after an intranasal administration of CS-8958, therapeutic administration of a single dose of CS-8958 showed superior efficacy to repeated administrations of zanamivir or oseltamivir in animal infection models for influenza A and B viruses. These include pandemic (2009) H1N1 virus and HPAI H5N1 virus. Prophylactic single administration of CS-8958, as early as 7 days prior to infection, also showed superior efficacy. Finally, the potential of a single inhalation of CS-8958 for influenza patients was demonstrated by clinical studies, and CS-8958 has been approved and is commercially available as Inavir(®) (Daiichi Sankyo Co., Ltd, Tokyo) in Japan.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Guanidines; Humans; Influenza, Human; Mice; Neuraminidase; Orthomyxoviridae; Oseltamivir; Pandemics; Prodrugs; Pyrans; Rats; Sialic Acids; Zanamivir

Laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. Like zanamivir, laninamivir is administered to patients by inhalation of dry powder. To date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. To better mimic the delivery action of laninamivir in humans, we assessed the applicability of a Dry Powder Insufflator™ (DPI) as a delivery method for laninamivir octanoate (LO) in ferrets to determine the effectiveness of this drug in reducing influenza A and B virus infections. In vitro characterisation of the DPI showed that both the small particle sized LO (0.7-6.0μm diameter) and the large particle sized lactose carrier (20-100μm diameter) were effectively discharged. However, LO delivered to ferrets via the DPI prior to infection with either A(H1N1)pdm09 or B viruses had a limited effect on nasal inflammation, clinical symptoms and viral shedding compared to placebo. Our preliminary findings indicate the feasibility of administering powder drugs into ferrets, but a better understanding of the pharmacokinetics and pharmacodynamics of LO in ferrets following delivery by the DPI is warranted prior to further studies.

Topics: Administration, Inhalation; Animals; Antiviral Agents; Disease Models, Animal; Drug Carriers; Ferrets; Guanidines; Orthomyxoviridae Infections; Placebos; Powders; Pyrans; Sialic Acids; Zanamivir

Laninamivir, a potent neuraminidase (NA) inhibitor, is an active metabolite of laninamivir octanoate (code name: CS-8958) which is a long acting NA inhibitor and is commercially available under the brand name Inavir in Japan to complete the treatment of influenza by a single inhalation. It is supposed that the long acting character is provided by the long retention of laninamivir in the respiratory tract after intranasal administration of laninamivir octanoate in mice and with stable binding of laninamivir to NA of various influenza viruses such as N1, N2 subtypes and NA of B virus. Peramivir, another NA inhibitor, is also approved in Japan as a single intravenous infusion. In spite of the quick disappearance of peramivir from the blood after injection, the reason treatment can be completed by a single administration is thought to be that peramivir showed stable binding to NA with N9 subtype. Therefore, the stable binder, laninamivir is possibly effective by a single intravenous administration in the mouse model infected with influenza viruses. A single intravenous administration of laninamivir and peramivir at 30mg/kg significantly prolonged mice survival at a comparable level in the mouse lethal model infected with the A/PR/8/34 (H1N1) virus. Also, a single intravenous administration of laninamivir and peramivir significantly suppressed virus proliferation in the lungs of mice infected with influenza B virus. Thus, laninamivir may be effective by a single intravenous infusion in treating influenza, the same as peramivir.

Topics: Administration, Intravenous; Animals; Antiviral Agents; Disease Models, Animal; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Mice; Mice, Inbred BALB C; Pyrans; Sialic Acids; Zanamivir

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for use for the treatment and prophylaxis of influenza. We have reported on laninamivir (code name, R-125489), a novel neuraminidase inhibitor, and have discovered that the laninamivir prodrug CS-8958 worked as a long-acting neuraminidase inhibitor in a mouse influenza virus infection model when it is intranasally administered. In this study, CS-8958 was administered just once 7 days before infection and showed significant efficacy in vivo. The efficacy of a single administration of CS-8958 after viral infection was then compared with that of repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets. CS-8958 showed efficacy superior or similar to the efficacies of the two licensed NA inhibitors. CS-8958 also significantly reduced the titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model. These results suggest that since CS-8958 is characteristically long lasting in the lungs, it may be ideal for the prophylaxis and treatment of influenza.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Ferrets; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Mice; Mice, Inbred BALB C; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Prodrugs; Treatment Outcome; Zanamivir