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Baloxavir marboxil

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This is an old revision of this page, as edited by 2601:246:c700:19d:a893:d336:57fe:e91c (talk) at 20:39, 8 January 2020 (Corrected issue with Shionogi numbers in drugbox. Added a resistance sentence to the lead, because this is what everyone doing research on this is talking about. Added further discovery chemistry information, including the fact that the onmarket drug is a prodrug (as well as the compounds abbreviations and synonyms that appear in its many publications).). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Baloxavir marboxil
Clinical data
Trade namesXofluza
Other namesBXM (S-033188)
BXA (S-033447)
AHFS/Drugs.comMonograph
MedlinePlusa618062
License data
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
CAS Number
PubChem CID
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H23F2N3O7S
Molar mass571.55 g·mol−1
3D model (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 trade/brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B. It was approved for medical use in both Japan and in the United States in 2018, and is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual.

Baloxavir marboxil (BXM) was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). BXA 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.

BXM was developed for the market by Shionogi Co., a Japanese pharmaceutical company, and Switzerland-based Roche AG.[1] The names under which BXM and BXA appear in Shionogi research reporting are S-033188 and S-033447, respectively.

Medical use

Baloxavir marboxil, sold under the trade name "Xofluza", is an influenza medication, an antiviral,[citation needed] that is taken as a single dose tablet, by mouth, by individuals that are 12 years of age or older that have presented symptoms of this infection for "no more than 48 hours".[2]

Side effects

Common side effects following the single dose administration of baloxavir were diarrhea and bronchitis.[3][better source needed] Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.[4]

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.[4] There is continuing research into and clinical concern over the resistance appearing in patients, in response to treatment with this drug.[5][6][7]

Approval

Japan's Ministry of Health, Labour and Welfare (JMHLW) and the U.S. Food and Drug Administration (FDA) approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric patients with uncomplicated influenza (Trial 1, 1518T0821 and Trial 2, NCT02954354), involving 1119 patients.[2][8][better source needed][verification needed] Both trials included clincal sites and patients in Japan, with Trial 2 adding clinical locations in the United States.[2]

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 outpatients by about one day compared to a placebo treatment group, and comparable to what was seen for a oseltamivir treatment group.[verification needed] On the first day after baloxavir was started in its treatment group of patients, viral loads decreased more than in patients 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.[4][verification needed][verification needed]

Baloxavir marboxil was approved for sale in Japan in February 2018.[9][better source needed] On October 24, 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people 12 years of age and older who have been symptomatic for no more than 48 hours.[3] 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 2019.[3][verification needed] Specifically, the FDA approved the use of Xofluza for people at high risk of developing influenza-related complications.[10]

Mechanism of action

Baloxavir marboxil is an influenza therapeutic agent, specifically, an enzyme inhibitor targeting the influenza virus' cap-dependent endonuclease activity, one of the activities of the virus polymerase complex.[11] In particular, it inhibits a process known as cap snatching,[citation needed] wherein virus derives short, capped primers from host cell RNA transcripts, using them for polymerase-catalyzed synthesis of its needed viral mRNAs.[12][non-primary source needed] A polymerase subunit binds to the host pre-mRNAs at their 5′-caps, then the polymerase's endonuclease activity catalyzes its cleavage "after 10–13 nucleotides".[12][non-primary source needed] As such, its mechanism is distinct from neuraminidase inhibitors such as oseltamivir and zanamivir.[citation needed]

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 Shinogi 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.[13][better source needed][14][15][16][17][18]

Baloxavir marboxil (BXM) is a prodrug whose active agent, baloxavir acid (BXA) is released rapidly in vivo, as the hydrolysis of BXM is catalysed by arylacetamide deacetylases of cells of the blood, and in the liver and lumen of the small intestine.[19][20][21] The compound numbers for BXM and BXA used in publications by Shionogi and others during discovery and development (prior to assignment of a USAN name) were, respectively, S-033188 and S-033447.[22] As reported in a review of the patent literature, the 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.[19][23]

References

  1. ^ Branswell, Helen (27 June 2018). "A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S." STAT.
  2. ^ a b c FDA Staff (23 July 2019). "Drug Trial Snapshot: Xofluza". U.S. Food and Drug Administration (FDA). Retrieved 7 January 2020.
  3. ^ a b c "FDA approves new drug to treat influenza". U.S. Food and Drug Administration (FDA) (Press release). 24 October 2018. Archived from the original on 24 October 2019. Retrieved 23 October 2019.
  4. ^ a b c Hayden FG, Sugaya N, Hirotsu N, et al. (September 2018). "Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents". N. Engl. J. Med. 379 (10): 913–923. doi:10.1056/NEJMoa1716197. PMID 30184455.
  5. ^ https://www.fiercepharma.com/pharma/roche-s-flu-med-xofluza-drives-drug-resistance-and-may-be-a-bad-choice-for-kids-study-says
  6. ^ https://www.eurekalert.org/pub_releases/2019-11/uow-nfd111919.php
  7. ^ https://www.nature.com/articles/s41564-019-0609-0
  8. ^ https://www.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/
  9. ^ "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 – via www.publicnow.com.
  10. ^ "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.
  11. ^ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619696/
  12. ^ a b Dias A, Bouvier D, Crépin T, et al. (April 2009). "The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit". Nature. 458 (7240): 914–8. Bibcode:2009Natur.458..914D. doi:10.1038/nature07745. PMID 19194459.
  13. ^ MedKoo Staff (8 January 2020). "Baloxavir marboxil: Synthetic Routes [Five Tabs]". Hodoodo.com. Morrisville, NC: MedKoo Biosciences. Retrieved 8 January 2020.
  14. ^ Okamoto, Kazuya; Ueno, Tatsuhiko; Hato, Yoshio; Hakogi, Toshikazu; Majima, Shohei. Method for stereoselective preparation of substituted polycyclic pyridone derivative. Assignee Shionogi & Co., Ltd., Japan. WO 2019070059. (2019).
  15. ^ Kawai, Makoto; Tomita, Kenji; Akiyama, Toshiyuki; Okano, Azusa; Miyagawa, Masayoshi. Pharmaceutical composition containing polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors. Assignee Shionogi and Co., Ltd., Japan. JP 6249434. (2017).
  16. ^ Shibahara, Setsuya; Fukui, Nobuaki; Maki, Toshikatsu. Polycyclic pyridone derivative, crystal and preparation method thereof. Assignee Shionogi and Co., Ltd., Japan. JP 6212678. (2017).
  17. ^ Kawai, Makoto; Tomita, Kenji; Akiyama, Toshiyuki; Okano, Azusa; Miyagawa, Masayoshi. Preparation of polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors and prodrugs thereof. Assignee Shionogi and Co., Ltd., Japan. JP 5971830. (2016).
  18. ^ See also: Zhu, Xiaoyun; Jiang, Weiping. Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug. CN 108440564. (2018).
  19. ^ a b https://pubs.acs.org/doi/full/10.1021/acs.oprd.9b00144
  20. ^ https://www.nature.com/articles/s41598-019-53945-1
  21. ^ https://link.springer.com/article/10.1007/s40261-018-0697-2
  22. ^ https://www.tandfonline.com/doi/abs/10.1080/13543784.2019.1606210
  23. ^ https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-02-0182

Further reading

External links

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