Journal articles: 'Baloxavir'

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Sato, Masatoki, Emi Takashita, Masahiko Katayose, Kenji Nemoto, Nobuko Sakai, Koichi Hashimoto, and Mitsuaki Hosoya. "Detection of Variants With Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018–2019 Influenza Season." Journal of Infectious Diseases 222, no. 1 (February 8, 2020): 121–25. http://dx.doi.org/10.1093/infdis/jiaa061.

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Abstract During the 2018–2019 influenza seasons, we detected reduced baloxavir marboxil (baloxavir) susceptible variants with I38S or I38T amino acid substitutions on the PA subunit of influenza virus ribonucleic acid polymerase in 7 of 18 baloxavi-treated children and found that virus titer rebounded in some of these children with variants. We also found fever durations to be similar between patients with or without the variants, but the patients with variants shed the virus 3 days longer and took longer to improve clinical symptoms than those without variants. The emergence of these variants should be monitored during future influenza seasons.

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Ando, Yoshinori, Takeshi Noshi, Kenji Sato, Toru Ishibashi, Yuki Yoshida, Takahiro Hasegawa, Motoyasu Onishi, et al. "Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection." Journal of Antimicrobial Chemotherapy 76, no. 1 (October 10, 2020): 189–98. http://dx.doi.org/10.1093/jac/dkaa393.

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Abstract Background Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. Objectives We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. Methods BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5–50 mg/kg q12h), subcutaneous baloxavir acid (0.25–8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. Results Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. Conclusions PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

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Taieb, Vanessa, Hidetoshi Ikeoka, Fang-Fang Ma, Katarzyna Borkowska, Samuel Aballea, Keiko Tone, and Nobuo Hirotsu. "A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients." Terapevticheskii arkhiv 92, no. 11 (December 26, 2020): 122–31. http://dx.doi.org/10.26442/00403660.2020.11.000870.

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Aim. Baloxavir marboxil (baloxavir) is the first cap-dependent endonuclease inhibitor being studied for the treatment of influenza in single oral dosing regimen. This network meta-analysis (NMA) evaluated the efficacy and safety of baloxavir compared to other antivirals for influenza in otherwise healthy patients. Methods. A systematic literature review was performed on 14 November 2016 in Medline, Embase, CENTRAL, and ICHUSHI to identify randomized controlled trials assessing antivirals for influenza. A NMA including 22 trials was performed to compare the efficacy and safety of baloxavir with other antivirals. Results. The time to alleviation of all symptoms was significantly shorter for baloxavir compared to zanamivir (difference in median time 19.96 h; 95% CrI [3.23, 39.07]). The time to cessation of viral shedding was significantly shorter for baloxavir than zanamivir and oseltamivir (47.00 h; 95% CrI [28.18, 73.86] and 56.03 h [33.74, 87.86], respectively). The mean decline in virus titer from baseline to 24 h was significantly greater for baloxavir than for the other drugs. Other differences in efficacy outcomes were not significant. No significant differences were found between baloxavir and the other antivirals for safety, except total drug-related adverse events where baloxavir demonstrated a decrease compared to oseltamivir and laninamivir. Conclusion. The NMA suggests that baloxavir demonstrated better or similar efficacy results compared to other antivirals with a comparable safety profile. Baloxavir led to a significant decrease in viral titer versus zanamivir, oseltamivir and peramivir and decreased viral shedding versus zanamivir and oseltamivir.

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Baker, Danial E. "Baloxavir Marboxil." Hospital Pharmacy 54, no. 3 (April 1, 2019): 165–69. http://dx.doi.org/10.1177/0018578719841044.

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Each month, subscribers to The Formulary Monograph Service receive 5 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.

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Shah, Sunish, Dayna McManus, Nika Bejou, Samad Tirmizi, Ginger E. Rouse, Steven M. Lemieux, Diana Gritsenko, and Jeffrey E. Topal. "Clinical outcomes of baloxavir versus oseltamivir in patients hospitalized with influenza A." Journal of Antimicrobial Chemotherapy 75, no. 10 (July 26, 2020): 3015–22. http://dx.doi.org/10.1093/jac/dkaa252.

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Abstract Objectives To date, clinical trials evaluating baloxavir have excluded patients hospitalized with influenza infection and therefore this study sought to evaluate the efficacy of baloxavir in inpatients with influenza A. Methods This study was a multicentre, retrospective chart review of adult patients admitted to the hospital within the Yale New Haven Health System who received oseltamivir or baloxavir for the treatment of influenza A. Patients were screened for inclusion between January 2018 and April 2018 in the oseltamivir group, while patients in the baloxavir group were screened for inclusion between January 2019 and April 2019. Influenza A diagnosis was confirmed by RT–PCR using a nasopharyngeal swab specimen. Results Of the 2392 patients assessed, 790 met the inclusion criteria. There were 359 patients who received baloxavir and 431 patients who received oseltamivir. Patients who received baloxavir were younger compared with those who received oseltamivir [median = 69 (IQR = 57–81) years versus 77 (IQR = 62–86) years; P < 0.001]. Patients who received baloxavir had no significant difference in hospital length of stay [median = 4 (IQR = 3–6) days versus 5 (IQR = 3–6) days; P = 0.45] or 30 day all-cause mortality [12 (3.3%) versus 26 (6%); P = 0.079] compared with those who received oseltamivir. However, patients who received baloxavir had a significantly faster time to hypoxia resolution [median = 51.7 (IQR = 25.3–89.3) h versus 72 (IQR = 37.5–123) h; P < 0.001]. Conclusions The results of this study support the use of baloxavir for the treatment of influenza A in hospitalized patients with the potential benefit of a faster time to resolution of hypoxia.

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ter Horst, Sebastiaan, Yaiza Fernandez-Garcia, Marcella Bassetto, Stephan Günther, Andrea Brancale, Johan Neyts, and Joana Rocha-Pereira. "Enhanced efficacy of endonuclease inhibitor baloxavir acid against orthobunyaviruses when used in combination with ribavirin." Journal of Antimicrobial Chemotherapy 75, no. 11 (August 7, 2020): 3189–93. http://dx.doi.org/10.1093/jac/dkaa337.

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Abstract Objectives Baloxavir acid is an endonuclease inhibitor approved for use against influenza. We evaluated whether this compound also targets the endonuclease domain of orthobunyaviruses and therefore could potentially be used against orthobunyavirus infections. Methods We performed a thermal shift assay and a fluorescence resonance energy transfer (FRET)-based nuclease monitoring assay using the La Crosse virus (LACV) endonuclease and baloxavir acid to prove their interaction and identify an inhibitory effect. Their interaction was further studied in a docking simulation using Glide SP. We show that baloxavir acid inhibits the viral replication of Bunyamwera virus (BUNV)–mCherry in vitro using high-content imaging and virus yield assay. Lastly, we investigated the use of baloxavir acid in combination with ribavirin in vitro by implementing the Zero Interaction Potency response surface model. Results We show that baloxavir acid augments LACV enzyme’s melting temperature with ΔTm 9.5 ± 0.4°C and inhibited substrate cleavage with IC50 0.39 ± 0.03 μM. Moreover, our docking simulation suggests that baloxavir acid is able to establish an efficient binding with the LACV endonuclease. In the cell-based assay, we observed that baloxavir acid and ribavirin inhibited BUNV–mCherry with an EC50 of 0.7 ± 0.2 μM and 26.6 ± 8.9 μM, respectively. When used in combination, we found a maximum synergistic effect of 8.64. Conclusions The influenza endonuclease inhibitor baloxavir acid is able to bind to and interfere with the endonuclease domain of orthobunyaviruses and yields a more potent antiviral effect than ribavirin against BUNV–mCherry. The combination of both compounds results in a more potent antiviral effect, suggesting that these molecules could potentially be combined to treat orthobunyavirus-infected patients.

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Yoshino, Yusuke, Keita Misu, Yoshitaka Wakabayashi, Yasuo Ota, and Takatoshi Kitazawa. "2644. Evaluation of Clinical Course and Heath-Related Quality-of-Life Following Treatment with Oseltamivir, Laninamivir, and Baloxavir Marboxil in Adult Patients with Seasonal Influenza: Prospective Observational Study." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S925. http://dx.doi.org/10.1093/ofid/ofz360.2322.

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Abstract Background Influenza is currently being treated in Japan with 4 types of neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir marboxil. Among these, baloxavir marboxil is the newest agent and currently available in limited countries, while the clinical efficacy of this drug in the real world remains to be determined. Methods Adult patients with seasonal influenza during the 2018–2019 winter season, who received either oseltamivir (75 mg twice daily for 5 days), laninamivir (40 mg once), or baloxavir marboxil (40 or 80 mg once) at their physician’s discretion in one hospital, were enrolled. The course of the symptoms including fever were surveyed by questionnaire. Health-related quality-of-life (HRQOL) was also examined by using Short Form-8 before and 7 days after admission. The main study endpoints were the time to defervescence and the extent of improvement of HRQOL after treatment initiation. Welch’s t-test and Fisher exact test were used for statistical analysis. Results Forty-two patients (oseltamivir group; n = 12, laninamivir group; n = 16, baloxavir group; n = 14) could be followed up. There were no significant differences in clinical backgrounds of all groups. Although there were no significant differences between the oseltamivir and each other groups with the time of defervescence, the average time to defervescence in the baloxavir group was shorter than that in the oseltamivir group (average ± standard deviation; 1.57 ± 0.76 vs. 2.33 ± 1.23 days, P = 0.0853). There were significant differences between the baloxavir and laninamivir groups (2.50 ± 1.26 days, P = 0.0231). There were no significant differences between each group with respect to the change of HRQOL and the time of clearing of other symptoms. Conclusion Regarding the antipyretic effect, baloxavir marboxil is clinically superior to laninamivir. Although there was no significant difference between the baloxavir group and the oseltamivir group with respect to the time to defervescence, baloxiavir marboxil also might be clinically superior to oseltamivir because baloxavir marboxil has an advantage over oseltamivir with respect to medication adherence. Disclosures All authors: No reported disclosures.

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Kiso, Maki, Seiya Yamayoshi, Yuri Furusawa, Masaki Imai, and Yoshihiro Kawaoka. "Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil." Viruses 11, no. 11 (November 15, 2019): 1066. http://dx.doi.org/10.3390/v11111066.

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Viral neuraminidase inhibitors show limited efficacy in mice infected with H7N9 influenza A viruses isolated from humans. Although baloxavir marboxil protected mice from lethal challenge infection with a low pathogenic avian influenza H7N9 virus isolated from a human, its efficacy in mice infected with a recent highly pathogenic version of H7N9 human isolates is unknown. Here, we examined the efficacy of baloxavir marboxil in mice infected with a highly pathogenic human H7N9 virus, A/Guangdong/17SF003/2016. Treatment of infected mice with a single 1.5 mg/kg dose of baloxavir marboxil protected mice from the highly pathogenic human H7N9 virus infection as effectively as oseltamivir treatment at 50 mg/kg twice a day for five days. Daily treatment for five days at 15 or 50 mg/kg of baloxavir marboxil showed superior therapeutic efficacy, largely preventing virus replication in respiratory organs. These results indicate that baloxavir marboxil is a valuable candidate treatment for human patients suffering from highly pathogenic H7N9 virus infection.

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Selvanayagam, Stephen, Amy Kang, and David Ha. "Baloxavir Marboxil: A New Antiviral for Acute Influenza." Journal of Contemporary Pharmacy Practice 66, no. 4 (January 1, 2020): 33–38. http://dx.doi.org/10.37901/jcphp19-00004.

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Baloxavir is a newly approved, single-dose, oral influenza antiviral indicated for acute uncomplicated influenza in patients 12 years and older if symptomatic for less than 48 hours. The purpose of this article is to review currently available literature on the mechanism of action, pharmacokinetics, safety, and clinical and virologic efficacy of baloxavir. Its novel mechanism of action prevents influenza replication by targeting the viral cap-dependent endonuclease enzyme. In clinical trials baloxavir was shown to be superior to placebo and comparable to oseltamivir with regard to time to alleviation of symptoms and viral titer reduction and was well tolerated with minimal adverse effects. Baloxavir is a viable treatment option for acute uncomplicated influenza in certain age groups.

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Seldeslachts, Laura, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Lauren Van der Sloten, Stephanie Humblet-Baron, Lieve Naesens, et al. "Overcome Double Trouble: Baloxavir Marboxil Suppresses Influenza Thereby Mitigating Secondary Invasive Pulmonary Aspergillosis." Journal of Fungi 8, no. 1 (December 21, 2021): 1. http://dx.doi.org/10.3390/jof8010001.

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Influenza-associated pulmonary aspergillosis (IAPA) is a global recognized superinfection in critically ill influenza patients. Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is a newly approved anti-influenza therapeutic. Although the benefits as a treatment for influenza are clear, its efficacy against an influenza-A. fumigatus co-infection has yet to be determined. We investigated the therapeutic effect of baloxavir marboxil in a murine model for IAPA. Immunocompetent mice received intranasal instillation of influenza A followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Administration of baloxavir marboxil or sham was started at day 0, day 2 or day 4. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). In vivo imaging was supplemented with virological, mycological and biochemical endpoint investigations. We observed an improved body weight, survival and viral clearance in baloxavir marboxil treated mice. µCT showed less pulmonary lesions and bronchial dilation after influenza and after Aspergillus co-infection in a treatment-dependent pattern. Furthermore, baloxavir marboxil was associated with effective inhibition of fungal invasion. Hence, our results provide evidence that baloxavir marboxil mitigates severe influenza thereby decreasing the susceptibility to a lethal invasive Aspergillus superinfection.

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Shah, Sunish, Dayna McManus, Nika Bejou, Samad Tirmizi, Ginger Rouse, Steven Lemieux, Diana Gritsenko, and Jeffrey E. Topal. "2645. Clinical Outcomes of Oseltamivir vs. Baloxavir in Patients Hospitalized with Influenza A." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S925. http://dx.doi.org/10.1093/ofid/ofz360.2323.

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Abstract Background Baloxavir marboxil is a new antiviral agent for the treatment of acute uncomplicated influenza in patients > 12 years of age who have been symptomatic for no more than 48 hours. However, clinical trials to date have excluded patients hospitalized with influenza infection. Methods This study was a multi-center, retrospective chart review of adult patients admitted to the hospital who received oseltamivir or baloxavir for the treatment of influenza A. Patients were screened for inclusion between January 2018 and February 2018 in the oseltamivir group while patients in the baloxavir group were screened for inclusion between January 2019 and February 2019. Patients who had influenza diagnosed after 48 hours from hospital admission, were not admitted to the hospital, received baloxavir and > 2 doses of oseltamivir during their hospital stay, received > 1 dose of baloxavir during admission for influenza, received influenza therapy prior to admission, died within 48 hours of presentation to the hospital, were asymptomatic at the time of antiviral therapy, or who had left the hospital against medical advice were excluded. Influenza A diagnosis was confirmed by RT–PCR using a nasopharyngeal swab specimen. The primary outcome was hospital length of stay (LOS). Results Of the 699 patients reviewed, 359 met inclusion criteria. There were 221 patients who received baloxavir and 138 patients who received oseltamivir. Patients who received oseltamivir were older (65 years [55–78] vs. 82 years [69–88], P < 0.01) and were less likely to have a Body Mass Index > 40 kg/m2 (26 [12%] vs. 7 [5%], P = 0.03) compared with the baloxavir group. For the primary outcome of LOS, the baloxavir group had a shorter LOS compared with oseltamivir (4 days [3–6] vs. 5 days [3–8], P = 0.02). Of the 272 patients who were hypoxic at the time of antiviral administration, the baloxavir group was more likely to resolve their hypoxia (145 [88%] vs. 84 [79%], P = 0.04) and had a shorter time to resolution of hypoxia (43 hours [22–78] vs. 81 hours [33–135], P < 0.001) compared with oseltamivir. Conclusion This study supports the use of baloxavir for the treatment of influenza A in hospitalized patients with possible benefits of reduced length of stay and faster time to resolution of hypoxia compared with oseltamivir. Disclosures All authors: No reported disclosures.

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Neuberger, Eddie, Chris Wallick, Devika Chawla, and Rita de Cassia Castro. "1518. Real-World Comparative Effectiveness of Baloxavir Marboxil versus Oseltamivir on Influenza-Related Complication and Resource Utilization." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S761—S762. http://dx.doi.org/10.1093/ofid/ofaa439.1699.

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Abstract Background In the 2018-19 season, there were an estimated 490,500 hospitalizations and 24,000 deaths from influenza in the US. Understanding how antiviral use affects rates and severity of complications is crucial to inform clinical practice. The objective of this study was to compare the frequency and costs of complications in influenza patients treated with baloxavir compared with oseltamivir-treated patients. This is one of the first analyses to examine comparative effectiveness of baloxavir in a real-world setting. Methods This retrospective cohort study used IBM MarketScan US administrative claims data from the 2018–19 influenza season. Patients were required to have an outpatient visit for influenza followed by a prescription for baloxavir or oseltamivir within 2 days. Baloxavir- and oseltamivir-treated patients were propensity score matched based on key baseline clinical and demographic characteristics. All-cause, all respiratory-related, and select respiratory-related (infection, asthma, and COPD) HRU in the 15 and 30 days following prescription fill were assessed using chi-square and Fisher’s exact tests for categorical measures and Wilcoxon signed-rank tests for counts and costs. Results We included 5,080 baloxavir-treated patients and 10,160 matched oseltamivir-treated patients in the analysis. Statistically significantly lower HRU was associated with baloxavir compared with oseltamivir therapy (15-day: respiratory-related ED visits, select respiratory-related ED visits and outpatient visits; 30-day: all-cause hospitalization, respiratory-related ED visits, select respiratory-related ED visits and outpatient visits (Table 1). Similarly, associated costs were generally lower in the baloxavir-treated group. Baloxavir-treated patients had lower mean per-patient all-cause 15-day costs (ED visits: $30 [95% CI: $21–$39] vs $42 [95% CI: $32–$51]; hospitalizations: $31 [95% CI: $6–$55] vs $74 [95% CI: $43–$104]) and 30-day costs (ED visits: $46 [95% CI: $35–$57] vs $67 [95% CI: $55–$79]; hospitalizations: $47 [95% CI: $15–$80] vs $119 [95% CI: $78–$161]). Table 1. Proportion of patients with at least one event Conclusion These findings suggest that treatment of influenza with baloxavir may improve outcomes and lower HRU costs compared with oseltamivir treatment. Disclosures Eddie Neuberger, PharmD, Genentech, Inc. (Employee) Chris Wallick, PharmD, MS, Genentech, Inc. (Employee) Devika Chawla, PhD MSPH, Genentech, Inc. (Employee) Rita de Cassia Castro, MD, Genentech, Inc. (Employee)

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Asher, Jason, Annabelle Lemenuel-Diot, Matthew Clay, David P. Durham, Luis Mier-y-Teran-Romero, Carlos J. Arguello, Sebastien Jolivet, et al. "Novel modelling approaches to predict the role of antivirals in reducing influenza transmission." PLOS Computational Biology 19, no. 1 (January 6, 2023): e1010797. http://dx.doi.org/10.1371/journal.pcbi.1010797.

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To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic–viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose–response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12–24 hours post symptom onset, the predicted transmission mitigation was 39.9–56.4% for baloxavir and 26.6–38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36–48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8–28.3% for baloxavir and 0.8–19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.

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Koshimichi, Hiroki, Sylvie Retout, Valérie F. Cosson, Stefan De Buck, Yoshiyuki Tsuda, Toru Ishibashi, and Toshihiro Wajima. "1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S559—S560. http://dx.doi.org/10.1093/ofid/ofz360.1400.

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Abstract Background Baloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients. Methods The population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients. Results A 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately. Conclusion The results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil. Disclosures All authors: No reported disclosures.

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Heo, Young-A. "Baloxavir: First Global Approval." Drugs 78, no. 6 (April 2018): 693–97. http://dx.doi.org/10.1007/s40265-018-0899-1.

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Kiso, Maki, Seiya Yamayoshi, Jurika Murakami, and Yoshihiro Kawaoka. "Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus." Journal of Infectious Diseases 221, no. 10 (December 14, 2019): 1699–702. http://dx.doi.org/10.1093/infdis/jiz665.

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Abstract Background Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses. Methods In this study, we examined the efficacy of baloxavir marboxil in nude mice that were immunologically deficient. Results Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment. Conclusions Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected.

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Abraham, George M., Jacob B. Morton, and Louis D. Saravolatz. "Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza." Clinical Infectious Diseases 71, no. 7 (February 5, 2020): 1790–94. http://dx.doi.org/10.1093/cid/ciaa107.

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Abstract Baloxavir marboxil (formerly S-033188) is a prodrug of baloxavir acid (S-033447) and inhibits cap-dependent endonuclease, an essential protein involved in the initiation of viral transcription by cleaving capped mRNA bound to PB2. Its adverse event profile is comparable to oseltamivir but is still vulnerable to resistance. The single-dose baloxavir marboxil is an appealing antiviral regimen for the treatment of influenza among outpatients when compared with longer, twice-daily regimens of oral and inhaled neuraminidase inhibitors. This review focuses on the mode of action, antiviral activity, pharmacokinetics, clinical indications, and safety profiles of this drug. Considerations for formulary addition and its place in therapy are also discussed.

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Ince, William L., Fraser B. Smith, Julian J. O’Rear, and Michael Thomson. "Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil." Journal of Infectious Diseases 222, no. 6 (April 7, 2020): 957–61. http://dx.doi.org/10.1093/infdis/jiaa164.

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Abstract Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.

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Ntem-Mensah, Afua Duker, Emily Heil, Mehrnaz Pajoumand, Ronald Rabinowitz, Samuel Galvagno, and Gregory Schrank. "2256. Baloxavir Marboxil in Combination with Oseltamivir in Two Critically Ill Patients with Influenza A (H1N1; 2009 strain) on Veno-Venous Extra-Corporal Membranous Oxygenation." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S772. http://dx.doi.org/10.1093/ofid/ofz360.1934.

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Abstract Background Currently, there are no clinical data regarding the use of baloxavir marboxil in patients with complicated influenza infection. A study in a mouse model of influenza A infection suggested that there may be a potential benefit of combination therapy with neuraminidase inhibitors. We present the first reported use of baloxavir marboxil in combination with oseltamivir in two critically ill patients requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO) support due to severe acute respiratory distress syndrome (ARDS) caused by influenza AH1N1 2009. Methods Cases: (1) 56-year-old man with a history of coronary artery disease who was vaccinated for flu this season, presented with 5 days of cough and dyspnea and required cannulation for VV-ECMO due to severe ARDS. He was placed on continuous renal replacement therapy (CRRT) for renal failure as well as vasopressor and inotropic support. Bronchoalveolar lavage (BAL) polymerase chain reaction (PCR) was positive for Influenza A H1N1 2009 strain. He received a dose of baloxavir 80 mg on Day 1 and a 7-day course of oseltamivir which was started on Day 0. Influenza PCR testing obtained 5 days after receipt of baloxavir was negative. The patient was decannulated on hospital day 7 and extubated at 14 days. (2) 50-year-old man with a history of hypertension and dyslipidemia who was not flu vaccinated, presented with symptoms of cough and dyspnea for 3 days. He was cannulated due to severe ARDS. He required CRRT for renal failure. BAL PCR tested positive for Influenza A H1N1 2009 strain. He was given two 80 mg doses of baloxavir on hospital days 1 and 5 and treated with oseltamivir for 10 days. Despite a negative PCR test for influenza on day 15, the patient remained critically ill on ECMO with multisystem organ failure. Results - Conclusion We describe the first reported clinical use of baloxavir in combination with oseltamivir for influenza A H1N1 infection in two critically ill patients with respiratory failure requiring VV ECMO. Further pharmacokinetic/pharmacodynamic analysis is needed to determine optimal dosing in critically ill patients, and those requiring CRRT. Baloxavir synergy with the neuraminidase inhibitors may be of benefit in critically ill patients, and additional prospective clinical study is needed. Disclosures All authors: No reported disclosures.

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Checkmahomed, Liva, Zeineb M’hamdi, Julie Carbonneau, Marie-Christine Venable, Mariana Baz, Yacine Abed, and Guy Boivin. "Impact of the Baloxavir-Resistant Polymerase Acid I38T Substitution on the Fitness of Contemporary Influenza A(H1N1)pdm09 and A(H3N2) Strains." Journal of Infectious Diseases 221, no. 1 (August 16, 2019): 63–70. http://dx.doi.org/10.1093/infdis/jiz418.

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Abstract Background Baloxavir is a cap-dependent inhibitor of the polymerase acid (PA) protein of influenza viruses. While appearing virologically superior to oseltamivir, baloxavir exhibits a low barrier of resistance. We sought to assess the impact of the common baloxavir-resistant I38T PA substitution on in vitro properties and virulence. Methods Influenza A/Quebec/144147/2009 (H1N1)pdm09 and A/Switzerland/9715293/2013 (H3N2) recombinant viruses and their I38T PA mutants were compared in single and competitive infection experiments in ST6GalI-MDCK cells and C57/BL6 mice. Virus titers in cell culture supernatants and lung homogenates were determined by virus yield assays. Ratios of wild-type (WT) and I38T mutant were assessed by digital RT-PCR. Results I38T substitution did not alter the replication kinetics of A(H1N1)pdm09 and A(H3N2) viruses. In competition experiments, a 50%:50% mixture evolved to 70%:30% (WT/mutant) for A(H1N1) and 88%:12% for A(H3N2) viruses after a single cell passage. The I38T substitution remained stable after 4 passages in vitro. In mice, the WT and its I38T mutant induced similar weight loss with comparable lung titers in both viral subtypes. The mutant virus tended to predominate over the WT in mouse competition experiments. Conclusion The fitness of baloxavir-resistant I38T PA mutants appears relatively unaltered in seasonal subtypes warranting surveillance for its dissemination.

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Lee, Leo Y., Jie Zhou, Paulina Koszalka, Rebecca Frise, Rubaiyea Farrukee, Keiko Baba, Shahjahan Miah, et al. "Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model." PLOS Pathogens 17, no. 5 (May 6, 2021): e1009527. http://dx.doi.org/10.1371/journal.ppat.1009527.

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Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.

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Slomski, Anita. "Baloxavir Protects Against Household Influenza Spread." JAMA 324, no. 12 (September 22, 2020): 1129. http://dx.doi.org/10.1001/jama.2020.17522.

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Mahendro, Della Sulamita. "Penggunaan Antivirus untuk COVID-19." Cermin Dunia Kedokteran 48, no. 7 (July 1, 2021): 419. http://dx.doi.org/10.55175/cdk.v48i7.1459.

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<p>Corona Disease 2019 (COVID-19) ditetapkan sebagai pandemi pada Maret 2020. Hingga saat ini belum ada terapi yang tepat untuk mencegah dan mengobati COVID-19. Beberapa antivirus diteliti sebagai profilaksis dan terapi COVID-19, seperti Hydroxychloroquine, Chloroquine, Lopinavir/Ritonavir, Baloxavir, Umifenovir, Remdesivir, Favipiravir, Oseltamivir, Molnupiravir dan AT527.</p><p>Corona Disease 2019 (COVID-19) was declared a pandemic in March 2020. Until now, there is no appropriate therapy to prevent and treat COVID-19. Several antivirals are being studied as prophylaxis and treat COVID-19, including : Hydroxychloroquine, Chloroquine, Lopinavir/Ritonavir, Baloxavir, Umifenovir, Remdesivir, Favipiravir, Oseltamivir, Molnupiravir and AT527.</p>

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Dufrasne, François. "Baloxavir Marboxil: An Original New Drug against Influenza." Pharmaceuticals 15, no. 1 (December 24, 2021): 28. http://dx.doi.org/10.3390/ph15010028.

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Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It is well tolerated (more than 1% of the patients experienced diarrhea, bronchitis, nausea, nasopharyngitis, and headache), and both influenza A and B viruses are sensitive, although the B strain is more resistant due to variations in the amino acid residues in the binding site. The drug is now in post-marketing pharmacovigilance phase, and its interest will be especially re-evaluated in the future during the annual flu outbreaks. It has been also introduced in a recent clinical trial against COVID-19 with favipiravir.

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Hirotsu, Nobuo, Hiroki Sakaguchi, Chisako Sato, Toru Ishibashi, Keiko Baba, Shinya Omoto, Takao Shishido, et al. "Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes." Clinical Infectious Diseases 71, no. 4 (September 20, 2019): 971–81. http://dx.doi.org/10.1093/cid/ciz908.

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Abstract Background We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza. Methods This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1–11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration. Results Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9–62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer). Conclusions A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children. Clinical Trials Registration Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417).

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Świerczyńska, Magdalena, Dagmara M. Mirowska-Guzel, and Edyta Pindelska. "Antiviral Drugs in Influenza." International Journal of Environmental Research and Public Health 19, no. 5 (March 4, 2022): 3018. http://dx.doi.org/10.3390/ijerph19053018.

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Flu is a serious health, medical, and economic problem, but no therapy is yet available that has satisfactory results and reduces the occurrence of these problems. Nearly 20 years after the registration of the previous therapy, baloxavir marboxil, a drug with a new mechanism of action, recently appeared on the market. This is a promising step in the fight against the influenza virus. This article presents the possibilities of using all available antiviral drugs specific for influenza A and B. We compare all currently recommended anti-influenza medications, considering their mechanisms of action, administration, indications, target groups, effectiveness, and safety profiles. We demonstrate that baloxavir marboxil presents a similar safety and efficacy profile to those of drugs already used in the treatment of influenza. Further research on combination therapy is highly recommended and may have promising results.

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Mazuchowski, Michał, and Łukasz Puchała. "Baloxavir marboxil as a therapeutic option to treat influenza in Poland." Farmacja Polska 76, no. 8 (September 28, 2020): 438–41. http://dx.doi.org/10.32383/farmpol/127828.

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Uyeki, Timothy M. "Baloxavir for Postexposure Prophylaxis against Influenza in Households." New England Journal of Medicine 383, no. 4 (July 23, 2020): 389–90. http://dx.doi.org/10.1056/nejme2022702.

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Mushtaq, Ammara. "Baloxavir: game-changer or much ado about nothing?" Lancet Respiratory Medicine 6, no. 12 (December 2018): 903–4. http://dx.doi.org/10.1016/s2213-2600(18)30469-7.

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Fujita, Jiro. "Introducing the new anti-influenza drug, baloxavir marboxil." Respiratory Investigation 58, no. 1 (January 2020): 1–3. http://dx.doi.org/10.1016/j.resinv.2019.10.005.

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Shirley, Matt. "Baloxavir Marboxil: A Review in Acute Uncomplicated Influenza." Drugs 80, no. 11 (June 29, 2020): 1109–18. http://dx.doi.org/10.1007/s40265-020-01350-8.

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Portsmouth, Simon, Keiko Kawaguchi, Takeki Uehara, and Frederick G. Hayden. "Comment to: Baloxavir efficacy in North American Adults." European Journal of Internal Medicine 72 (February 2020): 99–101. http://dx.doi.org/10.1016/j.ejim.2019.11.005.

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Rosenberg, Karen. "Baloxavir Effective in Preventing Influenza in Household Contacts." AJN, American Journal of Nursing 120, no. 11 (November 2020): 1. http://dx.doi.org/10.1097/01.naj.0000721956.76718.33.

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Wang, Yiyun, Xiaofang Lv, Zihui Meng, Zhibin Xu, Zhonghui Zheng, Jiarong Li, and Min Xue. "Fast and Efficient Synthesis of Racemic Baloxavir Catalyzed by Strong Solid Acid under Microwave Conditions." Crystals 12, no. 7 (June 23, 2022): 891. http://dx.doi.org/10.3390/cryst12070891.

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The compound (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is the intermediate of baloxavir marboxil. In the literature, traditional heating methods and common acid catalysts are used, which result in long reaction times and a low yield. Therefore, finding an efficient and environmentally friendly synthetic route is necessary. In this study, (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-benzyloxy-3,4,12,12a-tetrahydro-1h-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 3) was synthesized using a sulfonate resin solid acid catalyst (HND-580) under microwave conditions. The benzyl group was removed without further purification, and an intermediate, racemic baloxavir, was obtained under microwave irradiation. The total yield of the two steps was 78%. This method greatly reduces the reaction time and improves production efficiency.

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Saim-Mamoun, Amel, Yacine Abed, Julie Carbonneau, and Guy Boivin. "Generation and Characterization of Drug-Resistant Influenza B Viruses Selected In Vitro with Baloxavir Acid." Pathogens 11, no. 9 (September 15, 2022): 1048. http://dx.doi.org/10.3390/pathogens11091048.

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Baloxavir marboxil (BXM) is an antiviral drug that targets the endonuclease of the influenza polymerase acidic (PA) protein. Antiviral resistance, mainly mediated by the I38T PA substitution, readily occurs in both A(H1N1) and A(H3N2) viruses following a single dose of BXM. Influenza B resistance to BXM remains poorly documented. We aimed to generate baloxavir-resistant contemporary influenza B/Yamagata/16/1988- and B/Victoria/2/1987-like viruses by in vitro passages under baloxavir acid (BXA) pressure to identify resistance mutations and to characterize the fitness of drug-resistant variants. Influenza B/Phuket/3073/2013 recombinant virus (rg-PKT13, a B/Yamagata/16/1988-like virus) and B/Quebec/MCV-11/2019 (MCV19, a B/Victoria/2/1987-like isolate) were passaged in ST6GalI-MDCK cells in the presence of increasing concentrations of BXA. At defined passages, viral RNA was extracted for sequencing the PA gene. The I38T PA substitution was selected in MCV19 after six passages in presence of BXA whereas no PA change was detected in rg-PKT13. The I38T substitution increased the BXA IC50 value by 13.7-fold in the MCV19 background and resulted in reduced viral titers compared to the wild type (WT) at early time points in ST6GalI-MDCK and at all time-points in human epithelial cells. By contrast, the I38T substitution had no impact on MCV19 polymerase activity, and this mutation was genetically stable over four passages. In conclusion, our results show a similar pathway of resistance to BXA in influenza B viruses highlighting the major role of the I38T PA substitution and suggest that I38T may differently impact the fitness of influenza variants depending on the viral type, subtype, or lineage.

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Baker, Jeffrey, Stanley L. Block, Balpreet Matharu, Laura Burleigh Macutkiewicz, Steffen Wildum, Sophie Dimonaco, Neil Collinson, Barry Clinch, and Pedro A. Piedra. "Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children." Pediatric Infectious Disease Journal 39, no. 8 (May 19, 2020): 700–705. http://dx.doi.org/10.1097/inf.0000000000002747.

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Yokoyama, Takato, Hiroki Sakaguchi, Toru Ishibashi, Takao Shishido, Pedro A. Piedra, Chisako Sato, Kenji Tsuchiya, and Takeki Uehara. "Baloxavir Marboxil 2% Granules in Japanese Children With Influenza." Pediatric Infectious Disease Journal 39, no. 8 (March 12, 2020): 706–12. http://dx.doi.org/10.1097/inf.0000000000002748.

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Hayden, Frederick G., Norio Sugaya, Nobuo Hirotsu, Nelson Lee, Menno D. de Jong, Aeron C. Hurt, Tadashi Ishida, et al. "Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents." New England Journal of Medicine 379, no. 10 (September 6, 2018): 913–23. http://dx.doi.org/10.1056/nejmoa1716197.

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Ikematsu, Hideyuki, Frederick G. Hayden, Keiko Kawaguchi, Masahiro Kinoshita, Menno D. de Jong, Nelson Lee, Satoru Takashima, Takeshi Noshi, Kenji Tsuchiya, and Takeki Uehara. "Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts." New England Journal of Medicine 383, no. 4 (July 23, 2020): 309–20. http://dx.doi.org/10.1056/nejmoa1915341.

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Kikuchi, Toshiaki, and Akira Watanabe. "Baloxavir heralds a new era in influenza virus biology." Respiratory Investigation 57, no. 1 (January 2019): 1–2. http://dx.doi.org/10.1016/j.resinv.2018.10.002.

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O’Hanlon, Ryan, and Megan L. Shaw. "Baloxavir marboxil: the new influenza drug on the market." Current Opinion in Virology 35 (April 2019): 14–18. http://dx.doi.org/10.1016/j.coviro.2019.01.006.

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Hussar, Daniel A., and Matthew R. Moyer. "Baloxavir marboxil, Fremanezumab-vfrm, Galcanezumab-gnlm, and Lofexidine hydrochloride." Journal of the American Pharmacists Association 59, no. 1 (January 2019): 141–44. http://dx.doi.org/10.1016/j.japh.2018.12.002.

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Taniguchi, Keiichi, Yoshinori Ando, Masanori Kobayashi, Shinsuke Toba, Haruaki Nobori, Takao Sanaki, Takeshi Noshi, et al. "Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection." Viruses 14, no. 1 (January 8, 2022): 111. http://dx.doi.org/10.3390/v14010111.

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Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.

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Checkmahomed, Liva, Blandine Padey, Andrés Pizzorno, Olivier Terrier, Manuel Rosa-Calatrava, Yacine Abed, Mariana Baz, and Guy Boivin. "In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses." Viruses 12, no. 10 (October 8, 2020): 1139. http://dx.doi.org/10.3390/v12101139.

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Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.

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Takashita, Emi, Takashi Abe, Hiroko Morita, Shiho Nagata, Seiichiro Fujisaki, Hideka Miura, Masayuki Shirakura, et al. "Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment." Antiviral Research 180 (August 2020): 104828. http://dx.doi.org/10.1016/j.antiviral.2020.104828.

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Koshimichi, Hiroki, Toru Ishibashi, and Toshihiro Wajima. "Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients." Journal of Pharmaceutical Sciences 108, no. 9 (September 2019): 3112–17. http://dx.doi.org/10.1016/j.xphs.2019.04.010.

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Fujita, Jiro. "Clinical application of baloxavir marboxil in the treatment of influenza." Respiratory Investigation 58, no. 5 (September 2020): 301–4. http://dx.doi.org/10.1016/j.resinv.2020.06.003.

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Twabela, Augustin, Masatoshi Okamatsu, Keita Matsuno, Norikazu Isoda, and Yoshihiro Sakoda. "Evaluation of Baloxavir Marboxil and Peramivir for the Treatment of High Pathogenicity Avian Influenza in Chickens." Viruses 12, no. 12 (December 8, 2020): 1407. http://dx.doi.org/10.3390/v12121407.

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Control measures in the case of high pathogenicity avian influenza (HPAI) outbreaks in poultry include culling, surveillance, and biosecurity; wild birds in captivity may also be culled, although some rare bird species should be rescued for conservation. In this study, two anti-influenza drugs, baloxavir marboxil (BXM) and peramivir (PR), used in humans, were examined in treating HPAI in birds, using chickens as a model. Chickens were infected with H5N6 HPAI virus and were treated immediately or 24 h from challenge with 20 mg/kg BXM or PR twice a day for five days. As per our findings, BXM significantly reduced virus replication in organs and provided full protection to chickens compared with that induced by PR. In the 24-h-delayed treatment, neither drug completely inhibited virus replication nor ensured the survival of infected chickens. A single administration of 2.5 mg/kg of BXM was determined as the minimum dose required to fully protect chickens from HPAI virus; the concentration of baloxavir acid, the active form of BXM, in chicken blood at this dose was sufficient for a 48 h antiviral effect post-administration. Thus, these data can be a starting point for the use of BXM and PR in treating captive wild birds infected with HPAI virus.

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Takashita, Emi, Shin Murakami, Yoko Matsuzaki, Seiichiro Fujisaki, Hiroko Morita, Shiho Nagata, Misa Katayama, et al. "Antiviral Susceptibilities of Distinct Lineages of Influenza C and D Viruses." Viruses 15, no. 1 (January 15, 2023): 244. http://dx.doi.org/10.3390/v15010244.

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The emergence and spread of antiviral-resistant influenza viruses are of great concern. To minimize the public health risk, it is important to monitor antiviral susceptibilities of influenza viruses. Analyses of the antiviral susceptibilities of influenza A and B viruses have been conducted globally; however, those of influenza C and D viruses are limited. Here, we determined the susceptibilities of influenza C viruses representing all six lineages (C/Taylor, C/Yamagata, C/Sao Paulo, C/Aichi, C/Kanagawa, and C/Mississippi) and influenza D viruses representing four lineages (D/OK, D/660, D/Yama2016, and D/Yama2019) to RNA polymerase inhibitors (baloxavir and favipiravir) by using a focus reduction assay. All viruses tested were susceptible to both drugs. We then performed a genetic analysis to check for amino acid substitutions associated with baloxavir and favipiravir resistance and found that none of the viruses tested possessed these substitutions. Use of the focus reduction assay with the genotypic assay has proven valuable for monitoring the antiviral susceptibilities of influenza C and D viruses as well as influenza A and B viruses. Antiviral susceptibility monitoring of all influenza virus types should continue in order to assess the public health risks posed by these viruses.

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Odnovorov, A. I., T. V. Grebennikova, and T. V. Pleteneva. "Specific Influenza Therapy: Current State and Prospects (Review)." Drug development & registration 9, no. 1 (February 26, 2020): 83–91. http://dx.doi.org/10.33380/2305-2066-2020-9-1-83-91.

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Introduction. Respiratory infections are among the leaders in morbidity and mortality worldwide. The most severe cases of the disease are most often caused by the flu virus. Currently, there are many ways of specific prevention and treatment of influenza infection, but their effectiveness is far from ideal. This is due to the high variability of the influenza virus and the subsequent occurrence of resistance to the drugs used. In this regard, the improvement and development of antiviral drugs is an urgent task.Text. Influenza virus is an RNA-containing virus that causes massive epidemics and pandemics. Specific influenza prophylaxis includes vaccination. However, antigenic variability of the virus reduces the effectiveness of the vaccine, which requires constant costly development of its more advanced modifications. Specific treatment for influenza infection includes several classes of drugs, such as neuraminidase (NA) inhibitors oseltamivir, zanamivir and M2 protein inhibitors amantadine, rimantadine. At one time, these drugs were quite effective. But the formed resistance of influenza viruses to these drugs requires the creation of new or modifications of existing antiviral agents. Among the new domestic developments of antiviral drugs, histidyl-1-adamantainethylamine, which is a modification of the rimantadine molecule, has shown sufficient antiviral activity at the stage of preclinical studies. A representative of another class of drugs is arbidol (umifenovir), an inhibitor of hemagglutinin (HA) of the influenza virus. According to studies, the drug has high profiles of efficacy and safety, but the recommendation of the World Health Organization is to continue clinical trials. Currently, clinical studies of new classes of drugs are underway – baloxavir marboxil and favipiravir. Baloxavir marboxyl is a prodrug that is converted in vivo to baloxavir, an inhibitor of cap-dependent endonuclease. Favipiravir is an inhibitor of RNA-dependent RNA polymerase. In vitro studies in cell culture and in vivo in laboratory animals have shown higher efficacy of these drugs than the above with minimal toxicity.Conclusion. The rapid evolution of the influenza virus leads to a gradual decrease in the effectiveness of modern antiviral drugs. New compounds targeting targets important for virus reproduction are in clinical trials. The future of the fight against influenza depends on the outcome of these tests, according to which the compounds can become effective drugs for the prevention and treatment of influenza.

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Journal articles on the topic 'Baloxavir'

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