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Influenza affects individuals of all ages and poses a significant threat during pandemics, epidemics, and sporadic outbreaks. Neuraminidase inhibitors (NAIs) are currently the first choice in the treatment and prevention of influenza, but their use can be hindered by viral resistance. This review summarizes current NAIs pharmacological profiles, their current place in therapy, and the mechanisms of viral resistance and outlines possible new indications, ways of administration, and novel candidate NAIs compounds. NAIs represent a versatile group of compounds with diverse administration methods and pharmacokinetics. While the prevalence of influenza virus resistance to NAIs remains low, there is heightened vigilance due to the pandemic potential of influenza. Several novel NAIs and derivatives are currently under assessment at various stages of development for the treatment and prevention of influenza. [ABSTRACT FROM AUTHOR]

September 2023 WHO convenes technical consultations (1) in February and September each year to recommend viruses for inclusion in influenza vaccines (2) for the northern hemisphere (NH) and southern hemisphere [...]

February 2023 WHO convenes technical consultations (1) in February and September each year to recommend viruses for inclusion in influenza vaccines (2) for the northern hemisphere (NH) and southern hemisphere [...]

September 2022 WHO convenes technical consultations (1) in February and September each year to recommend viruses for inclusion in influenza vaccines (2) for the northern hemisphere (NH) and southern hemisphere [...]

In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines [...]

Large scale investigation of the clinical effectiveness of neuraminidase inhibitors for circulating influenza viruses are important along with the surveillance of virus susceptibility in vitro. The duration of fever and other influenza symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2017/18 and 2018/19 influenza seasons and compared with the results of the previous six seasons. Influenza A(H1N1)pdm09, A(H3N2), and B were found in 14, 45, and 52 patients in the 2017/18 season and in 22, 62, and 0 in the 2018/19 season, respectively. The median duration of fever for B was significantly longer than for A(H1N1)pdm09 and A(H3N2) in the 2017/18 season (p = 0.0461) and for A(H3N2) than for A(H1N1)pdm09 in the 2018/19 season (p = 0.0290). However, the differences were subtle in both seasons for other symptoms, with no significant differences in their median duration in comparison of the circulating types/subtypes. Over the eight seasons with the previous six seasons added, the median durations of fever were consistently longer for B than for A, but the relation between the A subtypes was inconsistent. The median durations of fever were comparable over the eight seasons for the virus types/subtypes, as were the median durations of other symptoms. The percentage of febrile patients decreased in a similar pattern over the eight seasons for each type/subtype. The results confirmed that laninamivir has continued to be clinically effective against all types/subtypes of influenza viruses, with no safety issues. [ABSTRACT FROM AUTHOR]

Yasuhiro Kamioka,1,2 Shota Kashiwagura,1,2 Masafumi Seki1 1Department of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai City, Miyagi, Japan; 2Division of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDepartment of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-Ku, Sendai City, Miyagi 983-8612, JapanTel +81-22-259-1221Fax +81-22-290-8956Email m-seki@tohoku-mpu.ac.jpObjective: The use of baloxavir, a new anti-influenza agent, began in Japan from the 2018 to 2019 season and became the focus of attention due to its efficient viral reduction ability; therefore, we should know the prescription changes of anti-influenza agents.Methods: We analyzed the changes in the prescription of anti-influenza agents between the 2018– 19 season and the 2019– 20 season in our hospital.Results: The share of baloxavir was 15%, while the shares of oseltamivir and laninamivir were 42% and 31%, respectively in the 2018– 2019 season. However, in the 2019– 20 season, the share of baloxavir and laninamivir was reduced to 3% and 17%, respectively, in contrast to an increase in the share of oseltamivir (66%). The total prescription of anti-influenza agents for patients decreased in the 2019– 20 season (205 patients), compared with the 2018– 19 season (509 patients).Conclusion: These results suggest significant changes such as a reduction in the prescription of anti-influenza agents, especially baloxavir, likely due to the suspected prevalence of a baloxavir-resistant strain of influenza virus and the emergence of SARS-CoV-2 in Japan.Keywords: anti-influenza agents, oseltamivir, laninamivir, zanamivir, peramivir, novel coronavirus-2019, COVID-19

The cap-dependent endonuclease inhibitor baloxavir marboxil is approved in Japan for the treatment of influenza virus infection in patients >12 years of age and children In phase 3 trials, patients [...]

We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug. Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert. Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0–39.0) h in type A virus (785 patients), 45.0 (34.0–56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials. The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses. [ABSTRACT FROM AUTHOR]

Baloxavir marboxil (baloxavir) is a single-dose antiviral which was previously found to be a cost-effective alternative to laninamivir in otherwise healthy adults in Japan. This study aimed at investigating the cost-effectiveness of baloxavir versus laninamivir in patients with influenza at high risk for complications. A decision tree was utilized to estimate costs and health gains associated with the use of antivirals. A lifetime horizon was applied to capture the long-term impact of influenza complications, and other events with associated costs and health outcomes were accounted for one influenza season. The study population was stratified into three categories: adolescents and non-elderly adults with high-risk conditions (HRC), elderly without other HRC, and elderly with other HRC. The cost-effectiveness was assessed from a public healthcare payer's perspective. The duration of influenza symptoms, probabilities of complications and probabilities of adverse events were obtained from a clinical trial and network meta-analysis. The costs of influenza and adverse events management were derived from the JammNet claims database. Utility values were informed by the clinical trial data and literature. Sensitivity analyses were also performed. The baloxavir strategy was associated with higher costs (+¥144) and higher quality-adjusted life-years (QALYs) in adults with HRC, elderly without HRC and elderly with HRC (+0.00078, +0.00183 and +0.00350 respectively). The overall incremental cost/QALY for baloxavir versus laninamivir was ¥68,855, which was below the willingness-to-pay threshold of ¥5 million/QALY gained. Key drivers of the model results were the probability of pneumonia and bronchitis. The probability of baloxavir being cost-effective was 72%. This study suggests that influenza treatment with baloxavir is cost-effective compared with laninamivir in the adult high-risk population in Japan. [ABSTRACT FROM AUTHOR]

We aimed to investigate the association between anaphylaxis and anti-influenza drug use using the Japanese Adverse Drug Event Report (JADER) database, a national spontaneous reporting database in Japan. We surveyed registered cases from the JADER database between April 2004 and November 2019. The target drugs were five anti-influenza drugs, namely oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir. Adverse events associated with anaphylaxis, "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction," and "anaphylactoid shock," were evaluated. The association between anaphylaxis and anti-influenza drug use was assessed by calculating the reporting odds ratio (ROR) and information component (IC) as a measure of disproportionality. Signals were considered positive if the lower limit of the 95% confidence interval (CI) of ROR was > 1, and that of IC was > 0. The number of anaphylaxis cases associated with anti-influenza drug use was 199 (0.9%). Signals were detected for inhaled laninamivir (ROR: 4.24 [95% CI: 3.06-5.88], IC: 1.83 [1.35-2.30]), intravenous peramivir (ROR: 2.97 [2.11-4.17], IC: 1.40 [0.90-1.89]), and oral baloxavir (ROR: 3.05 [2.22-4.18], IC: 1.44 [0.98-1.90]). Conversely, signals were not detected for oral oseltamivir or inhaled zanamivir. Although zanamivir and laninamivir were used as dry powder inhalers containing lactose as an additive, they differed in terms of signal detection. Our analysis indicated that the signal of anaphylaxis may varies based on the main component or dosage form of each anti-influenza drug. Appropriate use of these drugs is essential to prevent anaphylaxis and improve health status. [ABSTRACT FROM AUTHOR]

Baloxavir marboxil (baloxavir) is a new oral antiviral for influenza types A and B. To determine the cost-effectiveness of baloxavir versus laninamivir in otherwise healthy (OwH) adults in Japan. A decision tree was utilized to describe the course of influenza and predict associated costs and quality-adjusted life-years (QALYs) over one year by antiviral. Costs were valued from the public healthcare payer perspective, including influenza test, antiviral acquisition, other medications, physician visits, other outpatient costs associated with influenza or drug-related adverse events (DRAEs), and hospitalizations. Resource utilization and unit costs were obtained from the analysis of the JammNet claims database. Health state utilities were obtained from a clinical trial of baloxavir and previous models, and were driven by influenza symptoms, DRAEs, and complications caused by influenza. Sensitivity analyses were also performed. The total payer expenditure per patient for baloxavir versus laninamivir was ¥9383 versus ¥9132. The additional acquisition costs of baloxavir were partly offset by the DRAE costs avoided. Baloxavir showed a small gain in QALYs versus laninamivir and the incremental cost per QALY gained (¥2,231,260) was lower than the considered willingness-to-pay threshold (¥5,000,000/QALY). Key model drivers were the probability of DRAEs and the duration of symptoms. The probability of baloxavir being cost-effective was 64%. This cost-effectiveness study on baloxavir suggests that it would be cost-effective compared to laninamivir in OwH adults in Japan. Further studies are needed in different settings such as high-risk population and with different comparators. [ABSTRACT FROM AUTHOR]

Laninamivir (LAN) is a long-acting neuraminidase (NA) inhibitor (NAI) with a similar binding profile in the influenza NA enzyme active site as those of other NAIs, oseltamivir (OS), zanamivir (ZAN), and peramivir, and may share common resistance markers with these NAIs. We screened viruses with NA substitutions previously found during OS and ZAN selection in avian influenza viruses (AIVs) of the N3 to N9 subtypes for LAN susceptibility. Of the 72 NA substitutions, 19 conferred resistance to LAN, which ranged from 11.2- to 549.8-fold-decreased inhibitory activity over that of their parental viruses. Ten NA substitutions reduced the susceptibility to all four NAIs, whereas the remaining 26 substitutions yielded susceptibility to one or more NAIs. To determine whether the in vitro susceptibility of multi-NAI-resistant AIVs is associated with in vivo susceptibility, we infected BALB/c mice with recombinant AIVs with R292K (ma81K-N3R292K) or Q136K (ma81K-N8Q136K) NA substitutions, which impart in vitro susceptibility only to LAN or OS, respectively. Both ma81KN3R292K and ma81K-N8Q136K virus-infected mice exhibited reduced weight loss, mortality, and lung viral titers when treated with their susceptible NAIs, confirming the in vitro susceptibility of these substitutions. Together, LAN resistance profiling of AIVs of a range of NA subtypes improves the understanding of NAI resistance mechanisms. Furthermore, the association of in vitro and in vivo NAI susceptibility indicates that our models are useful tools for monitoring NAI susceptibility of AIVs. [ABSTRACT FROM AUTHOR]

Abstract Background A dry powder inhaled formulation is used for the anti-influenza drug laninamivir octanoate hydrate (laninamivir). Although two successive inhalations (puffs) are recommended to minimize residual amounts of active ingredients, previous reports suggest that pediatric patients with low peak inspiratory flow are unable to inhale the active ingredient adequately. In the present study, we prospectively investigated the appropriate number of repeated inhalations of laninamivir dry powder and factors influencing the residual amount of ingredients in pediatric patients with influenza. Methods The study enrolled 64 patients receiving laninamivir dry powder inhaler (Inavir®) between January and March 2016 at Tsu emergency medical center/pediatric clinic and dental clinic. All patients enrolled used a laninamivir dry powder inhaler in four repeated inhalations, as instructed by a pharmacist. The residual amount of laninamivir dry powder was calculated by measuring the device weight before and after each inhalation and a residual amount of >20% was defined as an unsuccessful inhalation. Results The inadequate inhalation rate after two successive inhalations was 45%, and it decreased as number of inhalation repeats increased, reaching 23% after four successive inhalations. Peak inspiratory flow in patients with inadequate inhalation was significantly lower than that in patients with adequate inhalation, for all numbers of inhalation repeats analyzed. Receiver operating characteristic analyses indicated peak inspiratory flow cut-off values of 140, 120, 100, and 100 L/min at 1-4 successive inhalations, respectively. Conclusions The present findings suggest that a proportion of patients with low peak inspiratory flow were unable to inhale the active ingredient adequately when laninamivir dry powder inhaler was administered as two successive inhalations, as recommended in the instruction manual. Three or four repeated inhalations of laninamivir dry powder inhaler should be administered to pediatric patients with low peak inspiratory flow.

Laninamivir, a neuraminidase inhibitor (NAI), has been used for the treatment and prophylaxis of influenza A/B. To date, pneumonia has not been reported as an adverse effect of NAIs. Here, we report the first 2 cases of drug-induced pneumonitis after the administration of laninamivir octanoate (LO), a pro-drug of laninamivir. Case 1 reports a 20-year-old healthy woman presenting with LO-induced pneumonitis so severe that it was necessary for endotracheal intubation and administration of mechanical ventilator support. Steroids were used for the treatment of pneumonitis and rapid improvement was observed. Case 2 reports a 35-year-old healthy woman presenting with less severe LO-induced pneumonitis that improved without any treatment. In both cases, drug-induced lymphocyte stimulation tests (DLSTs) were positive. In the bronchoalveolar lavage (BAL) fluid, the proportion of eosinophils to lymphocytes was higher in Case 1. Conversely, the proportion of lymphocytes to eosinophils was higher in Case 2. Collectively, we determined 3 clinical issues: (1) LO could cause pneumonia; (2) BAL and DLST could be helpful in the diagnosis of LO-induced pneumonitis; and (3) LO-induced pneumonia could become severe, though steroids were effective in improving it. [ABSTRACT FROM AUTHOR]

Four neuraminidase (NA) inhibitors and an RNA synthesis inhibitor were recently approved and are currently in clinical use for influenza. Among NA inhibitors, oseltamivir phosphate (OSE, Tamiflu®) and zanamivir are approved worldwide, whereas peramivir and laninamivir octanoate (LAN, Inavir®) are regionally approved for human use. Therefore, OSE has been used to treat infections of highly pathogenic influenza viruses, such as H5N1 and H7N9, which caused epidemic in southeast Asia and Egypt, and China, respectively. Generally, OSE is administered twice daily for 5 days by oral administration, and LAN once by inhalation for completing influenza therapy. In this study, we compared the efficacy of OSE and LAN administered according to the regimens in mice infected with highly lethal influenza viruses. The drugs were administered at the early and late stages of infection, which correspond to mild and severe inflammation in the lungs, respectively. Based on the drugs' regimens for human, a single administration of LAN at both stages of inflammation showed superior efficacy to repeated administration of OSE. LAN, as in OSE, could also be efficacious in treating severe influenza in humans. [ABSTRACT FROM AUTHOR]

Background: The relative ability of neuraminidase inhibitors (NAIs) to reduce household influenza transmission when given to index patients is not established. Objectives: To compare daily secondary infection rates (SIR) of influenza A (A/H1pdm and A/H3) and B in households of index patients treated with oseltamivir, zanamivir, laninamivir, or peramivir. Patients/Methods: This Japanese, single‐center, prospective, observational study (UMIN‐CTR: UMIN000024650) enrolled index patients with confirmed influenza who were treated with an NAI during 6 influenza seasons (2010‐2016). Secondary infection patients were household members diagnosed with the same influenza subtype 1‐7 days after onset in the index patient. Daily SIR was calculated using a modified Reed‐Frost model. The rate of household members with secondary infection and proportion of households with any secondary infection were also calculated. Results: Index patients with influenza A (n = 1146) or B (n = 661) were enrolled (~3400 total index and secondary patients). Daily SIR for all virus subtypes was highest when oseltamivir was used (eg, unadjusted estimate: type A, 1.47% vs 0.71%‐1.13%; type B, 1.30% vs 0.59%‐0.88%). Pairwise comparisons revealed significant differences in daily SIR between NAIs for influenza type A, type B, and subtype A/H3; for example, for type A, SIR was significantly higher with oseltamivir than with peramivir or zanamivir. The rate of household members with secondary infection and proportion of households with any secondary infection also varied between NAIs. Conclusions: Neuraminidase inhibitors differed in their ability to reduce household influenza transmission; transmission was highest with oseltamivir. Physicians may consider effects on household transmission when deciding which NAI to prescribe. [ABSTRACT FROM AUTHOR]

Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.

September 2020 WHO convenes technical consultations (1) in February and September each year to recommend viruses for inclusion in influenza vaccines (2) for the northern and southern hemisphere influenza seasons [...]

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2016/17 influenza season and the results were compared with those of the 2011/12 to 2015/16 seasons. A total of 1278 patients were evaluated for the duration of fever and symptoms in the six studied seasons. In the 2016/17 season, the influenza types/subtypes of the patients were 6 A (H1N1)pdm09 (2.9%), 183 A (H3N2) (87.6%), and 20 B (9.6%). The respective median durations of fever for A (H1N1)pdm09, A (H3N2), and B were 38.0, 33.0, and 38.5 h, without significant difference (p = 0.9201), and the median durations of symptoms were 86.5, 73.0, and 99.0 h, with significant difference (p = 0.0342). The median durations of fever and symptoms after laninamivir inhalation were quite consistent for the six studied seasons for A (H1N1)pdm09, A (H3N2), and B, without any significant differences. The percentage of patients with unresolved fever patients displayed a similar pattern through the six studied seasons for all these virus types. There was no significant difference in the duration of fever or symptoms between the Victoria and Yamagata lineages in the 2016/17 season and those of the previous studied seasons. Over the seasons tested, ten adverse drug reactions (ADRs) were reported from 1341 patients. The most frequent ADR was diarrhea and all ADRs were self-resolving and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A (H1N1)pdm09, A (H3N2), and B, with no safety issues. [ABSTRACT FROM AUTHOR]

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014–2015 to 2016–2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients ( p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0–4 years was 2.89-times greater than that in patients aged 10–18 years ( p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5–9 years was 2.13-times greater than that in patients aged 10–18 years ( p = 0.012). [ABSTRACT FROM AUTHOR]

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2015–2016 influenza season in Japan, we measured the 50% inhibitory concentration (IC 50 ) of NAIs for influenza virus isolates and compared them with the results from the 2010–11 to 2014–15 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Influenza viruses were isolated: 210 influenza A(H1N1)pdm09 (67.3%), 20 A(H3N2) (6.4%), and 82 B (26.3%), and for the Victoria and Yamagata lineages the numbers were 53 (64.6%) and 28 (34.1%), respectively, with one unknown. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM). No isolate showed a very high IC50 for A(H3N2) or B. The ratios of geometric mean IC50 of the 2015–2016 influenza season to those of the 2010–2011 to 2014–2015 influenza seasons ranged from 0.62 to 1.78 for A(H1N1) pdm09. The range was 0.73–1.35 for A(H3N2) and 0.48–1.12 for B. No significant trend of increase or decrease in IC50 was found for any of the four NAIs. Although some isolates showed highly reduced sensitivity to oseltamivir among the A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2), and B viruses are susceptible to all four NAIs, with no trend toward decreased sensitivity. [ABSTRACT FROM AUTHOR]

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2015/16 influenza season, and the results were compared with those of the 2011/12 to 2014/15 seasons. A total of 1068 patients were evaluated for the duration of fever and symptoms in the five studied seasons. The influenza types/subtypes were 125 A(H1N1)pdm09 (62.2%), 17 A(H3N2) (8.5%), and 59 B (29.4%) in the 2015/16 season. The median durations of fever were 40.0, 41.0, and 47.0 h, and the median durations of symptoms were 87.0, 76.0, and 93.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively, with no significant difference. The median durations of fever were 52.0 and 46.0 h and the median durations of symptoms 93.0 and 88.0 h for the Victoria and Yamagata B lineages, respectively, with no significant difference. Fever resolution after laninamivir inhalation by the A(H1N1)pdm09 patients was similar in the 2013/14 and 2015/16 seasons. Fever resolution after laninamivir inhalation was similar in all comparisons of the 2011/12 to 2015/16 seasons for both A(H3N2) and B, with no significant difference among the five seasons. Over the seasons tested, eight adverse drug reactions (ADRs) were reported for 1128 patients. The most frequent ADR was diarrhea, and all ADRs were resolved and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A(H1N1)pdm09, A(H3N2), and B, with no safety issues. [ABSTRACT FROM AUTHOR]

The duration of fever and other symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2014–2015 influenza season and the results were compared with those of the previous three seasons, 2011–2012 to 2013–2014. From these four seasons, the data of 636 influenza A(H3N2) and 128 influenza B patients was available for analysis. No significant difference was found in their baseline characteristics. The median duration of fever for all A(H3N2) patients ranged from 32.0 to 41.0 h. The duration of fever in the 2014–2015 season was significantly shorter than that in the 2012–2013 and 2013–2014 seasons (p = 0.0204 and 0.0391, respectively), but the differences were within nine hours. The median duration of symptoms for A(H3N2) ranged from 80.0 to 89.0 h, with no significant difference among the four seasons (p = 0.2222). The median duration of fever for B patients ranged from 43.0 to 50.0 h, with no significant difference among the four seasons. The duration of the symptoms for B varied by season, but no significant difference was found among the four seasons. Over the four seasons, 44 adverse events were reported from among 921 patients, with all resolving without treatment. These results indicate the continuing effectiveness of laninamivir against influenza A(H3N2) and B, with no safety issues. It is unlikely that the clinical use of laninamivir has caused viral resistance in the currently epidemic viruses. [ABSTRACT FROM AUTHOR]

Background. A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, has been proven to be effective in the treatment of influenza but not for post-exposure prophylaxis. Methods. We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine if a single administration of laninamivir octanoate 40 mg was superior to placebo for post-exposure prophylaxis. Eligible participants who had cohabited with an influenza patient within 48 hours of symptom onset were randomly assigned (1:1:1) to 1 of 3 groups: 40 mg of laninamivir octanoate single administration (LO-40SD), 20 mg of laninamivir octanoate once daily for 2 days (LO-20TD), or placebo. The primary efficacy endpoint was the proportion of participants who developed clinical influenza (defined as influenza virus positive, an axillary temperature >37.5°C, and at least 2 symptoms) over a 10-day period. Results. A total of 803 participants were enrolled, with 801 included in the primary analysis. The proportions of participants with clinical influenza were 4.5% (12/267), 4.5% (13/269), and 12.1% (32/265) in the LO-40SD, LO-20TD, and placebo groups, respectively. A single administration of laninamivir octanoate 40 mg significantly reduced the development of influenza compared with placebo (P = .001). The relative risk reductions compared with the placebo group were 62.8% and 63.1% for the LO-40SD and LO-20TD groups, respectively. The incidence of adverse events in the LO-40SD group was similar to that of the LO-20TD and placebo groups. Conclusions. A single administration of laninamivir octanoate was effective and well tolerated as post-exposure prophylaxis to prevent the development of influenza. Clinical Trials Registration. JapicCTI-142679. [ABSTRACT FROM AUTHOR]

The current School Health and Safety Act in Japan states that children with influenza infection should stay home until day 6th after symptoms onset. This was an amendment of a previous version recommending school return on day 3 after defervescence. Here, we investigated the duration of fever and virus shedding after laninamivir treatment in 7 children infected with influenza A(H3N2) virus and 21 children with influenza B virus in relation to the school return timing recommended by the School Health and Safety Act during the 2011-2012 influenza season. Nasal discharge was collected on the first, second, and third hospital visits and virus titers were assessed by virus culture and real-time PCR. Duration of fever after laninamivir treatment was 1 day longer for influenza B than for influenza A(H3N2). Virus detection rates with 50% tissue culture infectious dose and viral RNA were highest at the first visit and gradually decreased at subsequent visits. Virus positivity rates were detectable at the time of defervescence in less than half of the enrolled patients (14.3-42.9%). Virus shedding rates were similarly low (0.0-19.0%) on day 3 or later from defervescence and on day 6 or later from fever onset (school return dates per the old and current School Health and Safety Act) regardless of the influenza type. In conclusion, despite the higher efficacy of laninamivir against A(H3N2) viruses than B viruses, viral shedding is low after return to school for both types, regardless of the version of the School Health and Safety Act. [ABSTRACT FROM AUTHOR]

The clinical outcome of laninamivir octanoate hydrate (laninamivir) in the Japanese 2013–2014 influenza season was investigated. A total of 235 patients were enrolled, of whom 222 were evaluated for the duration of fever and other symptoms. The types/subtypes were 101 A(H1N1)pdm09 (45.5%), 37 A(H3N2) (16.7%), and 84 B (37.8%). The median durations of fever were 32.0, 41.0, and 50.0 h, and the median durations of symptoms were 74.5, 85.0, and 95.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively. The differences among the three groups were not statistically significant. There was no significant difference in the duration of fever or symptoms between patients under 10 and 10 years or over. The median durations of fever were 46.0 and 58.0 h and the median durations of symptoms were 95.0 and 77.0 h for the Yamagata and Victoria lineages, respectively. The virus positive rates at day 5 were significantly different at 31.5% (28/89), 12.1% (4/33), and 34.7% (26/75) for the three type/subtypes, respectively. The virus positive rates for A(H1N1)pdm09 and B were significantly higher for the patients under 10 years than for the patients 10 years or older. (p = 0.0379 and 0.0320, respectively). No significant increase was found between the IC 50 of days 1 and 5. No adverse drug reactions associated with laninamivir were reported. These results indicate the continuing clinical utility of laninamivir against influenza, irrespective of the virus type/subtype or lineage, and that it is unlikely that the clinical use of laninamivir will lead to selection of resistant virus. [ABSTRACT FROM AUTHOR]

To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC 50 ) of neuraminidase inhibitors (NAIs) for the influenza virus isolates in the 2013–2014 influenza season and compared the results to those of the 2010–2011 to 2012–2013 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 327 influenza viruses were isolated: 172 influenza A(H1N1)pdm09 (52.6%), 49 A(H3N2) (15.0%), and 106 B (32.4%). Numbers of Victoria and Yamagata lineage isolates were 36 and 70, respectively. Two A(H1N1)pdm09 isolates showed a high IC 50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC 50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC 50 for A(H3N2) or B. The IC 50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010–2011 season (P < 0.05). The IC 50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012–2013 season (P < 0.001). The IC 50 of the NAIs for B except for oseltamivir were significantly lower than those of the 2012–2013 season (P < 0.001). Although there are some isolates that show highly reduced sensitivity to oseltamivir among A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2) and B viruses are susceptible to all four NAIs with no trend toward decreased sensitivity. [ABSTRACT FROM AUTHOR]

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 (0.7–6.0 μm diameter) and the large particle sized lactose carrier (20–100 μm 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. [ABSTRACT FROM AUTHOR]

Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations. [ABSTRACT FROM AUTHOR]

The neuraminidase (NA) inhibitors oseltamivir and zanamivir are administered twice daily for 5 days for treatment of influenza. Laninamivir is a 7-methoxy derivative of zanamivir, but a single dose is effective when taken as the laninamivir octanoate prodrug. We show here in IC 50 kinetics assays and a solid phase reactivation assay that compared to zanamivir laninamivir also demonstrates slow binding to but slower dissociation from multiple wild type NAs. A D197E mutation in an influenza B and an E119G in an N9 neuraminidase which confer 15- and 150-fold resistance to laninamivir result in faster binding and dissociation. Despite similar IC 50 s our assays demonstrate more rapid dissociation of laninamivir from clade 1 compared to 2 H5N1 NAs. [ABSTRACT FROM AUTHOR]

The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu ® ), zanamivir (Relenza ® ), laninamivir octanoate (Inavir ® ), and peramivir (Rapiacta ® ) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC 50 ) of each NAI for influenza virus isolates in the 2012–2013 influenza season and compared the results to those of the 2010–2011 and 2011–2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC 50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC 50 values for A(H3N2) and B were similar to those of the 2010–2011 and 2011–2012 seasons. No isolate showed an increased IC 50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC 50 values to increase at present. [ABSTRACT FROM AUTHOR]

The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012–2013 influenza season for comparison with that of the Japanese 2011–2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older ( p < 0.0001). No significant change in IC 50 value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose The purpose of this study is to assess pregnancy outcomes of women treated with a novel neuraminidase inhibitor, laninamivir, during pregnancy. Methods A retrospective review of pregnancy outcomes of 112 pregnant women who were given laninamivir for treatment of influenza was performed. Possible adverse events, including miscarriages, preterm birth, foetal malformation and any neonatal morbidity requiring treatment, were assessed. Results Seventeen, 39, 46 and 10 women were administered a single inhaled dose of 20 or 40 mg of laninamivir at gestational week (GW) 3-11, 12-21, 22-36 and 37 or more, respectively. One (1.8%) of 56 women with laninamivir at GW <22 experienced miscarriage at GW <12. The remaining 111 women gave birth to 111 viable infants but at preterm (GW <37) in nine (8.8%) of 102 women with laninamivir at GW <37. Three (2.7%) of the 111 newborns had malformations: forefoot varus deformity, foot polydactyly and cleft lip in one each born to a mother taking laninamivir at GW 6, 17 and 21, respectively. Five neonates (4.5%) were small for gestational age. Eleven (9.9%), five (4.5%) and no neonates required phototherapy for jaundice, transient respiratory supports for respiratory distress syndrome ( n = 2) or transient tachypnoea of the newborn ( n = 3), and glucose administration for hypoglycaemia, respectively. Conclusions Although this study included a small number of study women and no control women, the results suggested that maternal exposure to laninamivir did not increase the rate of adverse pregnancy and foetal outcomes. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and <1% (6/1238) of influenza B viruses had reduced or highly reduced peramivir inhibition, with single occurrence of variants containing I221T, A245T, K360E, A395E, D432G and a combined G145R+Y142H mutation. These data demonstrate that despite an increase in H275Y variants in 2011, there was no marked change in the frequency of peramivir- or laninamivir-resistant variants following the market release of the drugs in Japan in 2010. [ABSTRACT FROM AUTHOR]

The neuraminidase inhibitors oseltamivir phosphate (Tamiflu®), zanamivir (Relenza®), laninamivir octanoate (Inavir®), and peramivir (Rapiacta®) have been available for the treatment of influenza in Japan since 2010. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each drug for influenza virus isolates from the 2011-2012 influenza season. Specimens were obtained from patients prior to treatment. Viral isolation was done using Madine-Darby canine kidney cells, and the type and subtype of influenza A(H1N1)pdm09, A(H3N2), or influenza B were determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. The lineage of influenza B virus was determined by direct sequencing of the hemagglutinin gene. Influenza A(H3N2) and influenza B viruses were isolated in 283 and 42 patients, respectively, while no influenza A(H1N1)pdm09 virus was isolated. No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. IC50 values for A(H3N2) were similar between the 2010-2011 and 2011-2012 seasons. In contrast, the IC50 values for influenza B viruses in the 2011-2012 season to the four drugs were significantly lower than those found in the 2010-2011 season. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase in Japan at present. [ABSTRACT FROM AUTHOR]

Laninamivir octanoate hydrate (laninamivir) is a long-acting, single inhalation neuraminidase inhibitor that was approved in Japan in 2010 for the treatment of influenza A and B virus infection. We investigated the duration of fever and other symptoms after the initiation of laninamivir in the Japanese 2011-2012 influenza season. Virus isolation was done and the 50% inhibitory concentration (IC50) was measured for the virus isolates at days 1 and 5. For 211 patients (A(H3N2): 190, B: 21), the median durations of fever of A(H3N2) and B patients were 33.0 and 50.0 h, respectively (p = 0.0989). Fever was resolved within 72 h after inhalation by 89.7% of the A(H3N2) patients and by 81.0% of the patients with B. The median durations of symptoms for A(H3N2) and B patients were 89.0 and 94.0 h, respectively (p = 0.5809). On day 5, the influenza virus-positive rates for A(H3N2) and B patients were significantly different: 25.8% (40/155) and 70.6% (12/17), respectively (p < 0.0001). No significant change in IC50 value was found between day 1 and day 5 for any of the four tested neuraminidase inhibitors, and no IC50 value exceeded 50 nM. The incidence of adverse drug reactions was 1.3% (3/234), with no serious reactions reported. These results show that laninamivir was effective for the treatment of both influenza A(H3N2) and B in this study, with no safety issues. The clinical effectiveness of laninamivir for A(H3N2) was superior to that for B. [ABSTRACT FROM AUTHOR]

Influenza A and B viruses cause significant morbidity and mortality worldwide each year. The neuraminidase inhibitors (NAIs) are the most commonly used class of influenza antiviral drugs for the treatment of infected patients. In vitro studies have shown that influenza B viruses are significantly less susceptible to oseltamivir and other neuraminidase inhibitors compared with influenza A viruses. Following analysis of published clinical studies, we show that oseltamivir does appear to have lower effectiveness in patients infected with influenza B virus compared with influenza A infected patients, but due to insufficient studies on zanamivir, laninamivir or peramivir, it was not possible to conclude the relative effectiveness of these drugs against influenza A virus compared with B virus. [ABSTRACT FROM AUTHOR]

Highlights: [•] All NA inhibitors were administered once intravenously to examine in vivo efficacy. [•] The efficacy was assessed in an influenza A and B viruses infection mouse model. [•] Laninamivir tended to reduce the viral load compared to peramivir. [•] Laninamivir could be enough to treat influenza by a single injection like peramivir. [Copyright &y& Elsevier]

Highlights: [•] Susceptibility of influenza viruses to all four NAIs was determined by IC50 method. [•] Prevalence of oseltamivir-resistant A(H1N1)pdm09 viruses increased to 3%. [•] A novel I222T mutation in NA showed a reduction in susceptibility to all four NAIs. [•] No NAI resistance was found among influenza A(H3N2) and B viruses in this study. [ABSTRACT FROM AUTHOR]

Laninamivir octanoate, a long-acting neuraminidase inhibitor, is an effective treatment for influenza. However, its effectiveness for the prevention of influenza has not yet been demonstrated. We conducted a double-blind, multicenter, randomized, placebo-controlled trial to determine whether laninamivir octanoate was superior to a placebo for post-exposure prophylaxis of influenza in household contacts. Eligible participants, who were household members who did not have influenza and were in contact with an influenza-infected index patient, were randomly assigned (1:1:1) to one of three groups: 20 mg of laninamivir octanoate once daily for 2 days (LO-2), 20 mg of laninamivir octanoate once daily for 3 days (LO-3), or a placebo. The primary endpoint was the proportion of participants who developed clinical influenza during a 10-day period. A total of 1711 participants were enrolled, and 1451 participants were included in the primary analysis. The proportion of participants with clinical influenza was 3.9 % (19/487) in the LO-2 group, 3.7 % (18/486) in the LO-3 group, and 16.9 % (81/478) in the placebo group ( P < 0.001 for each of the laninamivir octanoate group). The relative risk reductions, compared with the placebo group, were 77.0 % [95 % confidence interval (CI) 62.7-85.8] and 78.1 % (95 % CI 64.1-86.7 %) for the LO-2 and LO-3 groups, respectively. The incidences of adverse events in the laninamivir octanoate groups were similar to that in the placebo group. The inhalation of 20 mg of laninamivir octanoate once daily for 2 or 3 days was well tolerated and effectively prevented the development of influenza in household contacts. [ABSTRACT FROM AUTHOR]

Background: Abnormal behavior and delirium are common in children with influenza. While abnormal behavior and delirium are considered to be associated with influenza encephalopathy, an increased risk of such neuropsychiatric symptoms in patients receiving neuraminidase inhibitor treatment is suspected. Laninamivir octanoate hydrate, recently approved in Japan, is a long-acting neuraminidase inhibitor. It is important to establish a safety profile for laninamivir early, based on post-marketing experiences. Methods: Spontaneous safety reports collected in the early post-marketing phase vigilance were analyzed. Adverse events of interest such as abnormal behavior/delirium, dizziness/vertigo, respiratory disorders, shock/syncope, and any other serious events were intensively reviewed by the Safety Evaluation Committee. Results: Abnormal behavior/delirium was a frequently reported event. Almost all the reported cases were considered to be due to influenza and not laninamivir. There were 32 cases of abnormal behavior/delirium that could lead to dangerous accidents, and these were observed more frequently in males and teenagers. Syncope probably related to the act of inhalation per se of laninamivir was reported during this survey. Conclusions: This safety review revealed that the safety profile of laninamivir for abnormal behavior/delirium and syncope was similar to that of other neuraminidase inhibitors. As stated in the labeling, teenage patients inhaling laninamivir should remain under constant parental supervision for at least 2 days and should be closely monitored for behavioral changes to prevent serious accidents associated with abnormal behavior/delirium. Furthermore, to avoid syncope because of inhalation, patients should be instructed to inhale in a relaxed sitting position. [ABSTRACT FROM AUTHOR]

Background No studies of the clinical symptoms before starting therapy or of the effectiveness of neuraminidase inhibitors (NAIs) have been carried out of the 2009-2010 and 2010-2011 seasons that compare A(H1N1)pdm09 or the three circulating types of influenza virus. Methods The clinical symptoms and duration of fever (body temperature ≥37·5°C) after the first dose of an NAI (oseltamivir, zanamivir, laninamivir) were analyzed. PCR was carried out for 365 patients with A(H1N1)pdm09 in the 2009-2010 season and for 388 patients with one of the three types of influenza circulating in the 2010-2011 season. IC50 for the three NAIs was also analyzed in 51 patients in the 2010-2011 season. Results The peak body temperature was significantly higher in 2010-2011 than in 2009-2010 for patients under 20 years with A(H1N1)pdm09, and in the 2010-2011 season for children 15 years or younger with A(H1N1)pdm09 than for those with other virus types. The percentage of A(H1N1)pdm09 patients with loss of appetite or fatigue was significantly higher in 2010-2011 than in the previous season. The duration of fever was not affected by the kind of NAI or by age in multiple regression analysis. The percentage of patients afebrile at 48 hours after the first dose of NAI was significantly higher for A(H1N1)pdm09 than for A(H3N2) (laninamivir) or B (oseltamivir and laninamivir). Conclusion Although the clinical symptoms of A(H1N1)pdm09 were slightly more severe in the 2010-2011 season, the effectiveness of the NAIs remained high in comparison with 2009-2010 and with other types of seasonal influenza. [ABSTRACT FROM AUTHOR]

Laninamivir octanoate hydrate (laninamivir) is a long-acting neuraminidase inhibitor which requires only a single inhaled dose to fully treat infection by the influenza virus. In Japan, this drug was launched in October 2010 as a new treatment for the influenza virus. A postmarketing surveillance study was conducted in the 2010/2011 influenza season to assess the efficacy of this drug in clinical settings. For 3542 patients evaluated for efficacy (type A, n = 3179; type B, n = 342, unknown type, n = 3), including the day of drug administration, the median duration to fever resolution was three days, and the median duration to relief from influenza symptoms was four days. Based on the judgment of participating physicians, the efficacy rate was 97.6 % for type A influenza, 93.3 % for type B influenza, and 100 % in unknown types. 'Treatment failure,' as judged by participating physicians, was most closely correlated with the inhalation status of laninamivir. Despite laninamivir requiring only the administration of a single dose, it was confirmed to be an effective treatment in more than 90 % of patients with type A or type B influenza virus infections. This drug was considered to be useful for the treatment of influenza infections due to ease of use and its improvement of compliance. It became clear that the efficacy of laninamivir depended strongly on the status of inhalation, and thus careful and detailed instructions on the correct method of inhalation were considered to be important in order to obtain reliable therapeutic effects. [ABSTRACT FROM AUTHOR]

Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t1/2β) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t1/2β of approximately 3.0 hours). Peramivir is slowly eliminated (t1/2β of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation. [ABSTRACT FROM AUTHOR]

Influenza infection tends to be severe in patients with chronic underlying diseases. This study evaluated the efficacy and safety of laninamivir octanoate, an inhaled neuraminidase inhibitor, for the treatment of influenza patients with chronic respiratory diseases; we conducted a double-blind, randomized controlled trial to compare the efficacy and safety of laninamivir octanoate and oseltamivir for the treatment of influenza in these patients. A total of 203 patients aged ≥20 years were randomized to receive either laninamivir octanoate or oseltamivir. The primary efficacy endpoint was the time to illness alleviation. This study is registered with JapicCTI; the registration number is JapicCTI-090940. The full analysis set (FAS) included a total of 201 patients (laninamivir group, n = 101; oseltamivir group, n = 100). Most patients had underlying bronchial asthma and 170 patients were infected with influenza A(H1N1)2009. The median time to illness alleviation was 64.7 h in the laninamivir group and 59.7 h in the oseltamivir group, with a difference of 5.0 h between the two groups (95 % confidence interval, −13.6 to 16.1 h). No adverse events specific to laninamivir octanoate were observed, and adverse events such as bronchospasm, which has been reported to be observed with other inhaled drugs related to laninamivir octanoate, did not occur. Laninamivir octanoate showed similar efficacy and safety to oseltamivir in the treatment of influenza, including that caused by influenza A(H1N1)2009, in patients with chronic respiratory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Laninamivir octanoate hydrate (laninamivir) is a long-acting neuraminidase inhibitor (NAI) that completes treatment with only a single inhalation. It was launched in Japan in October 2010 as an anti-influenza agent. A post-marketing surveillance study was conducted in the 2010/2011 influenza season to assess the safety of this drug in clinical settings. Adverse drug reactions (ADRs) were observed in 50 patients (59 events) out of 3542 patients subjected to safety evaluation (incidence 1.41%). Commonly reported ADRs were psychiatric disorders (abnormal behaviour, etc.), gastrointestinal disorders (diarrhoea, nausea, etc.) and nervous system disorders (dizziness, etc.), with incidences of 0.48% (n =17), 0.45% (n =16) and 0.17% (n =6), respectively. No serious ADRs occurred. ADRs usually emerged on the day on which laninamivir was inhaled (52.5%) and ADRs emerged within 3 days after inhalation in >90% of adversely affected patients. ADRs resolved or improved within 3 days in >85% of patients. The incidence of adverse events involving abnormal behaviour was 3.1% (30/959) among patients <10 years of age, 0.7% (8/1088) among patients aged 10–19 years, 0.1% (2/1431) among adult patients aged 20–64 years and 0.0% (0/64) among patients aged ≥65 years. It was confirmed that laninamivir is unlikely to cause delayed ADRs or a prolonged duration of ADRs despite this drug being a long-acting NAI. Furthermore, the incidence of ADRs was not found to have increased compared with that observed during clinical trials, and the types of ADR observed during this study were similar to those previously observed. Thus, laninamivir octanoate hydrate was confirmed to have no noticeable problem with safety. [Copyright &y& Elsevier]

Abstract: Influenza A H5N1 and pH1N1 viruses have broadly emerged and become widespread in various countries around the world. Oseltamivir, the most commonly used antiviral drug against the seasonal and pandemic influenza viruses, is targeted at the viral neuraminidase (NA), but some isolates of this virus have become highly resistant to this drug. The novel long-acting drug, laninamivir, was recently developed to inhibit influenza A and B viruses of either the wild-type (WT) or the oseltamivir resistant mutant of NA. To understand the high efficiency of laninamivir, all-atom molecular dynamics simulations were performed on the WT and H274Y mutant of H5N1 and pH1N1 NAs with laninamivir bound. As a result, the novel drug was found to directly interact with 11 binding residues mainly through salt bridge and hydrogen bond formation (as also seen by electrostatic contribution). These are comprised of 7 of the catalytic residues (R118, D151, R152, R224, E276, R292 and R371), and 4 of the framework residues (E119, W178, E227 and E277). Laninamivir showed a similar binding pattern to all four NAs, but strong hydrogen bonding interactions were only found in the WT strain, with a slightly lowered contribution at some drug contact residues being observed in the H274Y mutation. This is in good agreement with the experimental data that the H274Y mutant has a small increase (1.3–7.5-fold, which was not statistically significant) in the IC50 value of laninamivir. [Copyright &y& Elsevier]

The half maximal inhibitory concentration (IC) of four neuraminidase inhibitors (NAIs), oseltamivir, zanamivir, laninamivir, and peramivir; was measured using influenza viruses isolated in the 2010-2011 influenza season in Japan. Clinical samples for viral isolation were obtained from nasal aspiration, nasopharyngeal swab, or self-blown nasal discharge and cultured with Madin-Darby canine kidney cells. The type and subtype of H3N2 or B were determined by reverse transcriptase polymerase chain reaction (RT-PCR). For the A(H1N1)pdm09 virus, the subtype was determined by real-time RT-PCR. ICs to oseltamivir carboxylate, zanamivir, laninamivir, and peramivir were determined by a fluorescence-based neuraminidase inhibition assay. Influenza viruses were isolated from 269 patients. A(H1N1)pdm09, H3N2, and B were isolated from 185, 54, and 30 patients, respectively. The geometric means of IC for oseltamivir were 0.86 and 0.73 nM to A (H1N1) pdm09, except for the two outlier viruses described below and H3N2, respectively, and 33.12 nM for B. The geometric means of IC for the other three NAIs were lowest to A(H1N1)pdm09 and highest to B. Two A(H1N1)pdm09 isolates showed very high IC values for oseltamivir (840 and 600 nM) and peramivir (19 and 24 nM). No isolate showed significantly high IC values for zanamivir or laninamivir. Continuous surveillance against the emergence or spread of influenza virus with high IC values for anti-influenza drugs is important. [ABSTRACT FROM AUTHOR]

Oseltamivir and Zanamivir are the two main Neuraminidase inhibitors used for the treatment of Influenza. Oseltamivir resistance has been identified in non-pandemic influenza viruses, as well as H1N1 pandemic Influenza A viruses. Resistance is associated with increased morbidity, and poorer outcomes in severely immunocompromised hosts. Newer neuraminidase inhibitors, increased vaccination and combination therapy may be alternatives for the treatment of Influenza in this setting. [ABSTRACT FROM AUTHOR]