Baloxavir marboxil

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Baloxavir marboxil
Clinical data
Trade namesXofluza
Other namesBXM (S-033188), BXA (S-033447)
AHFS/Drugs.comMonograph
MedlinePlusa618062
License data
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Identifiers
  • ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazin-7-yl}oxy)methyl methyl carbonate
JSmol)
  • O=C(OCOC(C(C=C1)=O)=C(N1N([C@@H]2C3=CC=CC=C3SCC4=C(F)C(F)=CC=C24)[C@@]5([H])N6CCOC5)C6=O)OC
  • InChI=1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1
  • Key:RZVPBGBYGMDSBG-GGAORHGYSA-N

Baloxavir marboxil, sold under the brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B.[4] It was approved for medical use both in Japan and in the United States in 2018,[7][8][9] and is taken as a single dose by mouth.[4] It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual.[10][unreliable medical source?]

Baloxavir marboxil was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). Baloxavir acid then functions as enzyme inhibitor, targeting the influenza virus' cap-dependent endonuclease activity, used in "cap snatching" by the virus' polymerase complex, a process essential to its life-cycle.[11]

The most common side effects of baloxavir marboxil include diarrhea, bronchitis, nausea, sinusitis, and headache.[12]

The US Food and Drug Administration (FDA) considers baloxavir marboxil to be a first-in-class medication.[13]

Medical uses

Baloxavir marboxil is an influenza medication, an

antiviral,[14][4] for individuals who are twelve years of age or older,[5][14] that have presented symptoms of this infection for no more than 48 hours.[5][14][15] The efficacy of baloxavir marboxil administered after 48 hours has not been tested.[14]

In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications.[4][9]

In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu.[4][12]

In August 2022, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people five years of age and older after contact with an individual who has the flu.[4][16]

In the EU, baloxavir marboxil is indicated for the treatment of uncomplicated influenza and for post-exposure prophylaxis of influenza in individuals aged twelve years of age and older.[5]

Available forms

Baloxavir marboxil is available in tablet form and as granules for mixing in water.[12]

Resistance

In 2.2% of baloxavir recipients in the Phase II trial and in about 10% of baloxavir recipients in the Phase III trial, the infecting influenza strain had acquired resistance to the drug, due to variants of the polymerase protein displaying substitutions of isoleucine-38, specifically, the I38T, I38M, or I38F mutations.[17] There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug.[18][19][20]

Contraindications

Baloxavir marboxil should not be co-administered with dairy products, calcium-fortified beverages, or laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminum or zinc.[12]

Side effects

Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea.[4][15][7] Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.[17]

Mechanism of action

Baloxavir marboxil is an influenza therapeutic agent, specifically, an

neuraminidase inhibitors such as oseltamivir and zanamivir.[22]

Chemistry

Baloxavir marboxil is a substituted pyridone derivative of a polycyclic family, whose chemical synthesis has been reported in a number of ways by the company discovering it, Shionogi and Co. of Japan (as well as others); the Shionogi reports have appeared several times in the Japanese patent literature between 2016 and 2019, providing insight into possible industrial synthetic routes that may be in use.[23][24][25][26][27]

active moiety[28]

Baloxavir marboxil (BXM) is a prodrug whose active agent, baloxavir acid (BXA) is released rapidly in vivo, as the hydrolysis of baloxavir marboxil is catalyzed by

carbonic acid ester (carbonate) moiety of the prodrug—shown in the lower left-hand corner of the image above—was prepared during discovery and development research from a late stage 2-hydroxy-4-pyridone precursor by treatment with chloromethyl methyl carbonate.[29][33]

History

As of September 2018, in the only report of a Phase III randomized, controlled trial, baloxavir reduced the duration of influenza symptoms of otherwise healthy participants by about one day compared with a placebo treatment group, and comparable with what was seen for an oseltamivir treatment group.[15] On the first day after baloxavir was started in its treatment group of participants, viral loads decreased more than in participants in either the oseltamivir or placebo groups; however, after five days, the effect on viral load of the single dose of baloxavir was indistinguishable from the effect observed following the complete, 5-day regimen of oseltamivir in its treatment group.[17][verification needed]

Baloxavir marboxil was developed for the market by

Roche AG.[34] The names under which baloxavir marboxil and baloxavir acid appear in Shionogi research reporting are S-033188 and S-033447, respectively.[citation needed
]

Society and culture

Legal status

Japan's

better source needed][verification needed] Both trials included clinical sites and participants in Japan, with Trial 2 adding clinical locations in the United States.[4][15]

Baloxavir marboxil was approved for sale in Japan in February 2018.

better source needed] In October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people twelve years of age and older who have been symptomatic for no more than 48 hours.[7][8] The FDA application of baloxavir marboxil was granted priority review in the United States, and approval of Xofluza was granted to Shionogi & Co., Ltd. in October 2018.[7][8] Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications.[38] In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications.[9] In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu.[12]

Baloxavir marboxil was approved for medical use in Australia in February 2020.[1]

The safety and efficacy of baloxavir marboxil, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 subjects where participants were assigned to receive either baloxavir marboxil, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms.[7] In both trials, subjects treated with baloxavir marboxil had a shorter time to alleviation of symptoms compared with subjects who took the placebo.[7] In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir marboxil and those who received the other flu treatment.[7]

The safety and efficacy of baloxavir marboxil for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, twelve years of age and older who were exposed to a person with influenza in their household, received either a single dose of baloxavir marboxil or a single dose of a placebo.[12] Of these 607 subjects, 303 received baloxavir marboxil and 304 received the placebo.[12] The trial's primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10.[12] Of those who received baloxavir marboxil, 1% of subjects met these criteria, compared to 13% of subjects who received a placebo for the clinical trial.[12]

Baloxavir marboxil was approved for medical use in the European Union in January 2021.[5]

References

  1. ^ a b c "Xofluza Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 2 March 2020. Archived from the original on 13 March 2020. Retrieved 16 August 2020.
  2. ^ "Xofluza Product information". Health Canada. 25 April 2012. Archived from the original on 12 August 2022. Retrieved 29 May 2022.
  3. ^ "Summary Basis of Decision (SBD) for Xofluza". Health Canada. 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  4. ^ a b c d e f g h i j "Xofluza- baloxavir marboxil tablet, film coated". DailyMed. 28 October 2019. Archived from the original on 28 October 2020. Retrieved 9 January 2020.
  5. ^ a b c d e "Xofluza EPAR". European Medicines Agency (EMA). 9 November 2020. Archived from the original on 30 January 2021. Retrieved 25 January 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ^ "Xofluza Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  7. ^ a b c d e f g "FDA approves new drug to treat influenza" (Press release). U.S. Food and Drug Administration (FDA). 24 October 2018. Archived from the original on 24 October 2019. Retrieved 23 October 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c "Drug Approval Package: Xofluza Film-Coated Tablets (Baloxavir marboxil)". U.S. Food and Drug Administration (FDA). 7 December 2018. Archived from the original on 26 July 2020. Retrieved 10 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  9. ^ a b c "FDA Approval Package for 210854Orig1s001" (PDF). U.S. Food and Drug Administration (FDA). 16 October 2019. Archived (PDF) from the original on 9 April 2021. Retrieved 30 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ^ "Baloxavir Marboxil for Uncomplicated Influenza: Mechanism of Action & Side Effects". Huateng Pharma. Archived from the original on 24 February 2021. Retrieved 29 May 2020.
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  12. ^ a b c d e f g h i "FDA Expands Approval of Influenza Treatment to Post-Exposure Prevention" (Press release). U.S. Food and Drug Administration (FDA). 23 November 2020. Archived from the original on 23 November 2020. Retrieved 23 November 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ^ New Drug Therapy Approvals 2018 (PDF) (Report). U.S. Food and Drug Administration (FDA). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ^ a b c d "Baloxavir Marboxil Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. 19 August 2019. Archived from the original on 7 October 2019. Retrieved 9 January 2020.
  15. ^ a b c d e Food and Drug Administration (23 July 2019). "Drug Trial Snapshot: Xofluza". U.S. Food and Drug Administration (FDA). Archived from the original on 12 December 2019. Retrieved 7 January 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  16. ^ "Genentech Announces FDA Approval of Xofluza to Treat Influenza in Children Aged Five and Older" (Press release). Genentech. 11 August 2022. Archived from the original on 12 August 2022. Retrieved 11 August 2022 – via Business Wire.
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  19. ^ "New flu drug drives drug resistance in influenza viruses". EurekAlert (Press release). Archived from the original on 16 January 2021. Retrieved 8 January 2020.
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  24. ^ JPWO 2018030463, Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M, "Pharmaceutical composition containing polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors.", published 2017, assigned to Shionogi and Co., Ltd., Japan. 
  25. ^ JPWO 2017221869, Shibahara S, Fukui N, Maki T, "Polycyclic pyridone derivative, crystal and preparation method thereof.", published 2017, assigned to Shionogi and Co., Ltd., Japan. 
  26. ^ JPWO 2016175224, Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M, "Preparation of polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors and prodrugs thereof.", published 2016, assigned to Shionogi and Co., Ltd., Japan 
  27. ^ CN 108440564, Zhu X, Jiang W, "Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug.", published 2018 
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  34. ^ Branswell H (27 June 2018). "A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S.". Stat. Archived from the original on 20 October 2020. Retrieved 28 June 2018.
  35. ^ "A Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Otherwise Healthy Patients With Influenza". ClinicalTrials.gov. 3 November 2016. Archived from the original on 21 January 2022. Retrieved 11 August 2022.
  36. ^ Otake T (24 February 2018). "One-dose flu drug Xofluza gets nod from health ministry". Japan Times Online. Archived from the original on 2 November 2021. Retrieved 8 January 2020.
  37. ^ "Xofluza (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan" (Press release). Shionogi & Co., Ltd. 23 February 2018. Archived from the original on 20 January 2021. Retrieved 23 February 2018 – via publicnow.com.
  38. ^ "Genentech Announces FDA Approval of Xofluza (Baloxavir Marboxil) for People at High Risk of Developing Influenza-Related Complications" (Press release). Genentech. 17 October 2019. Archived from the original on 24 October 2019. Retrieved 23 October 2019 – via Business Wire.

Further reading

External links