Abstract
Pharmacokinetic profiles of laninamivir after a single inhalation of laninamivir octanoate (LO), a prodrug of laninamivir, using a newly developed easy-to-use inhaler were evaluated in healthy volunteers. LO appeared rapidly in plasma after an inhaled administration in healthy volunteers with a median value of tmax of 0.25 hr, and the plasma concentrations decreased below the detection limit after 24 hr of inhalation. The median tmax of laninamivir was 4.0 hr and laninamivir slowly declined after Cmax with a mean t1/2 of 66.6 and 74.4 hr at a dose of 20 mg and 40 mg, respectively. The average AUC0-inf and Cmax for LO and laninamivir almost increased proportionally with the dose. The mean cumulative excretion amounts of LO in urine for 144 hr after inhaling 20 mg or 40 mg dose of LO were 4.7 and 5.5% of the dose, respectively, and those of laninamivir were 19.2 and 23.3%, respectively. No clinical or laboratory adverse experiences were reported and no subject discontinued because of an adverse experience. As plasma concentrations of both LO and laninamivir revealed a similar pattern between using the prototype and this new inhaler, LO exhibited potential for long lasting anti-influenza activity using this easy-to-use inhaler.
Highlights
Laninamivir (Figure 1) is a new neuraminidase inhibitor which has been shown to be sensitive against various influenza A and B viruses, including subtypes N1 to N9, oseltamivir-resistant viruses [1] and new swine-origin H1N1 strains like A/California/04/09 in vitro and in vivo [7, 8]
A single inhalation of laninamivir octanoate (LO) reduced the duration of influenza illness significantly, compared with oseltamivir, against H1N1 virus with the H274Y mutation in pediatric patients [17]
This long-acting characteristic of LO is supported by the long plasma half-life of laninamivir (~3 days) after a single inhaled administration, which might predominantly reflect the slow release from retaining tissues to plasma [5,6]
Summary
Laninamivir (Figure 1) is a new neuraminidase inhibitor which has been shown to be sensitive against various influenza A and B viruses, including subtypes N1 to N9, oseltamivir-resistant viruses [1] and new swine-origin H1N1 strains like A/California/04/09 in vitro and in vivo [7, 8]. LO conferred more potent and longlasting protection to mice against H5N1 influenza viruses, including oseltamivir-resistant mutants than did oseltamivir [7]. After being intranasally administered [14C]LO, the radioactivity was retained in the respiratory tract over extended time periods with high levels in the trachea and lung equal to those of laninamivir over 24 hours postdose [9]. Long retention in the trachea and lung was observed after intratracheal administration to rats, and plasma concentration of laninamivir in rats was slowly eliminated. Hydrolysis of LO in the respiratory tract was observed in human lung S9 in vitro by various kinds of esterase (unpublished data). Its half-life was considerably longer than that after intravenous administration of laninamivir [10]
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