Prodrug, Laninamivir Octanoate, a Long-Acting NeuraminidaseInhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers

Yoshiba, Satoshi; Okabe, Hiromi; Ishizuka, Hitoshi

doi:10.4172/jbb.1000048

Cited by 10 publications

(8 citation statements)

References 19 publications

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“…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). Moreover, laninamivir bound to viral neuraminidase in vitro more stably than did other neuraminidase inhibitors, including oseltamivir, zanamivir, and peramivir (13).…”

mentioning

confidence: 97%

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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confidence: 97%

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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“…In humans as well, after a single inhalation of LO (40 mg), laninamivir was generated and highly maintained in the ELF (Ishizuka et al, 2012), exceeding the in vitro 50% inhibitory concentrations for influenza viral neuraminidases over 10 days (Yamashita et al, 2009). A slow elimination of laninamivir was also observed in the systemic circulation, with an elimination half-life (t 1/2 ) of approximately 3 days (Ishizuka et al, 2009;Yoshiba et al, 2011). These favorable pharmacokinetic characteristics are considered to result in the long-lasting effect.…”

Section: Introductionmentioning

confidence: 85%

Identification of Bioactivating Enzymes Involved in the Hydrolysis of Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, in Human Pulmonary Tissue

et al. 2014

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Laninamivir octanoate (LO) is an octanoyl ester prodrug of the neuraminidase inhibitor laninamivir. After inhaled administration, LO exhibits clinical efficacy for both treatment and prophylaxis of influenza virus infection, resulting from hydrolytic bioactivation into its pharmacologically active metabolite laninamivir in the pulmonary tissue. In this study, we focused on the identification of LOhydrolyzing enzymes from human pulmonary tissue extract using proteomic correlation profiling-a technology integration of traditional biochemistry and proteomics. In a single elution step by gelfiltration chromatography, LO-hydrolyzing activity was separated into two distinct peaks, designated as peak I and peak II. By mass spectrometry, 1160 and 1003 proteins were identified and quantitated for peak I and peak II, respectively, and enzyme candidates were ranked based on the correlation coefficient between the enzyme activity and the proteomic profiles. Among proteins with a high correlation value, S-formylglutathione hydrolase (esterase D; ESD) and acyl-protein thioesterase 1 (APT1) were selected as the most likely candidates for peak I and peak II, respectively, which was confirmed by LO-hydrolyzing activity of recombinant proteins. In the case of peak II, LO-hydrolyzing activity was completely inhibited by treatment with a specific APT1 inhibitor, palmostatin B. Moreover, immunohistochemical analysis revealed that both enzymes were mainly localized in the pulmonary epithelia, a primary site of influenza virus infection. These findings demonstrate that ESD and APT1 are key enzymes responsible for the bioactivation of LO in human pulmonary tissue.

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“…On the basis of these findings, the authors suggested that because laninamivir octanoate is administered as a single dose for therapeutic purposes, accumulation is unlikely to occur in patients with renal insufficiency [123]. More recently, an alternative delivery device was used in healthy adults, which led to increases in the peak plasma concentration and the AUC of approximately 2-to 3-fold in comparison with the results of the earlier phase I trial [124]. These findings suggest that newer inhalers may yield higher systemic exposure, for which additional study is necessary to determine whether dosing adjustments are warranted for patients with end-stage renal disease.…”

Section: Laninamivirmentioning

confidence: 92%

Clinical Pharmacokinetics of Inhaled Antimicrobials

2015

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Administration of inhaled antimicrobials affords the ability to achieve targeted drug delivery into the respiratory tract, rapid entry into the systemic circulation, high bioavailability and minimal metabolism. These unique pharmacokinetic characteristics make inhaled antimicrobial delivery attractive for the treatment of many pulmonary diseases. This review examines recent pharmacokinetic trials with inhaled antibacterials, antivirals and antifungals, with an emphasis on the clinical implications of these studies. The majority of these studies revealed evidence of high antimicrobial concentrations in the airway with limited systemic exposure, thereby reducing the risk of toxicity. Sputum pharmacokinetics varied widely, which makes it challenging to interpret the result of sputum pharmacokinetic studies. Many no vel inhaled antimicrobial therapies are currently under investigation that will require detailed pharmacokinetic studies, including combination inhaled antimicrobial therapies, inhaled nanoparticle formulations of several antibacterials, inhaled non-antimicrobial adjuvants, inhaled antiviral recombinant protein therapies and semi-synthetic inhaled antifungal agents. Additionally, the development of new inhaled delivery devices, particularly for mechanically ventilated patients, will result in a pressing need for additional pharmacokinetic studies to identify optimal dosing regimens.

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Prodrug, Laninamivir Octanoate, a Long-Acting NeuraminidaseInhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers

Cited by 10 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

Identification of Bioactivating Enzymes Involved in the Hydrolysis of Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, in Human Pulmonary Tissue

Clinical Pharmacokinetics of Inhaled Antimicrobials

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