CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract

Koyama, Kumiko; Takahashi, Makoto; Oitate, Masataka; Nakai, Naoko; Takakusa, Hideo; Miura, Shinichi; Okazaki, Osamu

doi:10.1128/aac.00731-09

Cited by 70 publications

(61 citation statements)

References 19 publications

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“…High-level accumulation of laninamivir in the lung, with a long t 1/2 , was observed after intranasal or intratracheal administration of LO to mice or rats (14,15). PK studies of humans also showed a long t 1/2 of laninamivir in plasma (10,11), which is reflected by the slow release from retaining tissues to plasma and by the slow formation of laninamivir from LO in ELF and AM.…”

Section: Discussionmentioning

confidence: 92%

“…This long-acting characteristic of LO is partly supported by the pharmacokinetics (PK) of laninamivir. Laninamivir was retained in the trachea and lungs over long periods after a single intranasal/intratracheal administration of LO in mice and rats (14,15). In humans, the PK of laninamivir after an inhaled dose of LO revealed a long plasma half-life in healthy young adults and in subjects with renal impairment (10,11,26).…”

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confidence: 99%

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Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

Ishizuka

Toyama

Yoshiba

et al. 2012

Antimicrob Agents Chemother

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A single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single-center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 g/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

Ishizuka

Toyama

Yoshiba

et al. 2012

Antimicrob Agents Chemother

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“…4). The half-life of zanamivir in the respiratory tract after inhalation or intranasal administration was estimated to be 2.8 h in humans (21), and it seemed to be less than 1 h in mice (16). The half-life of oseltamivir carboxylate in blood after the oral administration of oseltamivir phosphate was 7.0 h in rats (19).…”

Section: Discussionmentioning

confidence: 99%

“…We found a new strong neuraminidase inhibitor, laninamivir (code name, R-125489), and reported that CS-8958 (laninamivir octanoate or the laninamivir prodrug) worked as a longacting neuraminidase inhibitor (12,16,23). Laninamivir potently inhibited the neuraminidase activities of various influenza A and B viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses (23), as well as pandemic 2009 H1N1 virus (14).…”

mentioning

confidence: 99%

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Kubo

Tomozawa

Kakuta

et al. 2010

Antimicrob Agents Chemother

121

103

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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.

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“…After a single intranasal/intratracheal administration of LO to mice and rats, the LO was efficiently converted/hydrolyzed to its active form laninamivir, and thereafter the generated laninamivir was retained over long periods in the respiratory tissues (Koyama et al, 2009(Koyama et al, , 2010. Moreover, it was confirmed in mice that this retention level was much higher than those after intranasal administration of laninamivir itself and zanamivir (Relenza; GlaxoSmithKline plc, London, UK) (Koyama et al, 2009). Such preferable pharmacokinetic characteristics were observed in humans as well.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

et al. 2012

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Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 mmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using 14 C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 mM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h 21, which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.

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CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract

Cited by 70 publications

References 19 publications

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

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