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→Resistance: Elevating the Resistance subsection to section status, because of the continuing importance of this matter.
Added Chemistry section. Moved the Resistance section to the point in the article below the Side effects section (because of the preeminence of adverse events data in drug approval). Moved the clinical trial content from the Medical uses section to the Approvals section, for editing or replacement by the alternative material (see Talk). Even if the blockquote is added, this pre-existing material needs to be integrated.
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{{Expert needed|Medicine|ex2=Chemistry|talk=|reason=the article fails to paint a complete picture of the benefits and drawbacks of the medication, and little is said about agent's discovery/chemistry; updated text from the secondary scientific literature is needed |date=January 2020}}
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'''Baloxavir marboxil''', sold under the brand name '''Xofluza''', is an antiviral medication for treatment of [[influenza A]] and [[influenza B]]. It is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day.
'''Baloxavir marboxil''', sold under the trade/brand name '''Xofluza''', is an antiviral medication for treatment of [[influenza A]] and [[influenza B]]. It is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day.


It was approved for medical use in the United States in 2018. It was developed by [[Shionogi]] Co., a [[Japan]]ese [[pharmaceutical]] company, and [[Hoffmann-La Roche|Roche AG]].<ref name=stat>{{cite web |title=A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S. |url=https://www.statnews.com/2018/06/27/flu-drug-single-pill/ |website=STAT |date=27 June 2018 | first=Helen | last=Branswell}}</ref>
It was approved for medical use in the United States in 2018. It was developed by [[Shionogi]] Co., a [[Japan]]ese [[pharmaceutical]] company, and [[Hoffmann-La Roche|Roche AG]].<ref name=stat>{{cite web |title=A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S. |url=https://www.statnews.com/2018/06/27/flu-drug-single-pill/ |website=STAT |date=27 June 2018 | first=Helen | last=Branswell}}</ref>


==Medical use==
==Medical use==
{{expand section | with=a full description of the medical use content that is standard to these sections | small = no}}
⚫
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. On the first day after baloxavir was started in its treatment group of patients, [[viral load]]s 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.<ref name=nejm>{{cite journal |vauthors=Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A |display-authors=3 |title=Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents |journal=N. Engl. J. Med. |volume=379 |issue=10 |pages=913–923 |date=September 2018 |pmid=30184455 |doi=10.1056/NEJMoa1716197}}</ref>{{verification needed|date=January 2020}}
Baloxavir marboxil, sold under the trade name "Xofluza", is an influenza medication, an [[antiviral]],{{cn}} 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".<ref name="FDA Snapshot">{{cite web | author = FDA Staff | date = July 23, 2019 | title=Drug Trial Snapshot: Xofluza | website=U.S. [[Food and Drug Administration]] (FDA) | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-xofluza | access-date=7 January 2020}}</ref>

==Side effects==
⚫
Common side effects following the single dose administration of baloxavir were diarrhea and bronchitis.<ref name=FDA>{{cite press release | title=FDA approves new drug to treat influenza | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 October 2018 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-url=https://web.archive.org/web/20191024055423/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}}</ref>{{better source|date=January 2020}} Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.<ref name=nejm/>


==Resistance==
==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.<ref name=nejm/>
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.<ref name=nejm/>


==Side effects==
== 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.<ref name="FDA Snapshot"/><ref>https://www.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/</ref>{{better source}}{{verification needed}} Both trials included clincal sites and patients in Japan, with Trial 2 adding clinical locations in the United States.<ref name="FDA Snapshot" />
⚫
Common side effects following the single dose administration of baloxavir were diarrhea and bronchitis.<ref name=FDA>{{cite press release | title=FDA approves new drug to treat influenza | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 October 2018 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-url=https://web.archive.org/web/20191024055423/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}}</ref>{{better source|date=January 2020}} Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.<ref name=nejm/>

⚫
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 load]]s 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.<ref name=nejm>{{cite journal |vauthors=Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A |display-authors=3 |title=Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents |journal=N. Engl. J. Med. |volume=379 |issue=10 |pages=913–923 |date=September 2018 |pmid=30184455 |doi=10.1056/NEJMoa1716197}}</ref>{{verification needed|date=January 2020}}{{verification needed}}

⚫
Baloxavir marboxil was approved for sale in Japan in February 2018.<ref>{{cite press release|url=http://www.publicnow.com/view/7E9FBF87835EEBAC31508CC4E1F96D3D77D54C0A|title=Xofluza (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan|date=23 February 2018|via=www.publicnow.com|publisher=[[Shionogi|Shionogi & Co., Ltd.]]}}</ref>{{better source}} 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.<ref name=FDA/> 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.<ref name=FDA/>{{verification needed}} Specifically, the FDA approved the use of Xofluza for people at high risk of developing influenza-related complications.<ref>{{cite press release | title=Genentech Announces FDA Approval of Xofluza (Baloxavir Marboxil) for People at High Risk of Developing Influenza-Related Complications | publisher=[[Genentech]] | via=Business Wire | date=17 October 2019 | url=https://www.businesswire.com/news/home/20191017005525/en | archive-url=https://web.archive.org/web/20191024061608/https://www.businesswire.com/news/home/20191017005525/en | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}}</ref>


== Mechanism of action ==
== Mechanism of action ==
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Baloxavir marboxil is an influenza therapeutic agent, specifically, an [[enzyme inhibitor]] targeting the influenza virus' [[Five-prime cap|cap]]-dependent [[ribonuclease|endonuclease]] activity,{{cn|date=January 2020}} one of the activities of the virus polymerase.{{cn|date=January 2020}} <!--TWO SENTENCES REMOVED HERE—ONE IRRELEVANT, ON DOSING, AND THE SECOND, EARLIER, PUT FORWARD [[pharmacodynamics]] AND OTHERWISE RESTATED THE OPENING SENTENCE, AND SO WAS SIMPLY WRONG, AND UNNECESSARY.--> In particular, it inhibits a process known as [[cap snatching]],{{cn|date=January 2020}} wherein virus derives short, capped [[primer]]s from host cell RNA transcripts, using them for polymerase-catalyzed synthesis of its needed viral [[mRNA]]s.<ref name=CusackNature2009>{{cite journal |vauthors=Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW |display-authors=3 |title=The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit |journal=Nature |volume=458 |issue=7240 |pages=914–8 |date=April 2009 |pmid=19194459 |doi=10.1038/nature07745|bibcode=2009Natur.458..914D }}</ref>{{primary source inline|date=January 2020}} 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".<ref name=CusackNature2009/>{{primary source inline|date=January 2020}} As such, its mechanism is distinct from [[neuraminidase inhibitors]] such as [[oseltamivir]] and [[zanamivir]].{{cn|date=January 2020}}
Baloxavir marboxil is an influenza therapeutic agent, specifically, an [[enzyme inhibitor]] targeting the influenza virus' [[Five-prime cap|cap]]-dependent [[ribonuclease|endonuclease]] activity,{{cn|date=January 2020}} one of the activities of the virus polymerase.{{cn|date=January 2020}} <!--TWO SENTENCES REMOVED HERE—ONE IRRELEVANT, ON DOSING, AND THE SECOND, EARLIER, PUT FORWARD [[pharmacodynamics]] AND OTHERWISE RESTATED THE OPENING SENTENCE, AND SO WAS SIMPLY WRONG, AND UNNECESSARY.--> In particular, it inhibits a process known as [[cap snatching]],{{cn|date=January 2020}} wherein virus derives short, capped [[primer]]s from host cell RNA transcripts, using them for polymerase-catalyzed synthesis of its needed viral [[mRNA]]s.<ref name=CusackNature2009>{{cite journal |vauthors=Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW |display-authors=3 |title=The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit |journal=Nature |volume=458 |issue=7240 |pages=914–8 |date=April 2009 |pmid=19194459 |doi=10.1038/nature07745|bibcode=2009Natur.458..914D }}</ref>{{primary source inline|date=January 2020}} 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".<ref name=CusackNature2009/>{{primary source inline|date=January 2020}} As such, its mechanism is distinct from [[neuraminidase inhibitors]] such as [[oseltamivir]] and [[zanamivir]].{{cn|date=January 2020}}


== Approval ==
==Chemistry==
{{expand section | with = a general description of the compound and class, and details regarding its discovery and process syntheses, etc. | small = no}}
⚫
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.<ref name="FDA Snapshot">{{cite web | author = FDA Staff | date = July 23, 2019 | title=Drug Trial Snapshot: Xofluza | website=U.S. [[Food and Drug Administration]] (FDA) | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-xofluza | access-date=7 January 2020}}</ref><ref>https://www.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/</ref>{{better source}}{{verification needed}} Both trials included clincal sites and patients in Japan, with Trial 2 adding clinical locations in the United States.<ref name="FDA Snapshot" />
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.<ref>{{cite web | author = MedKoo Staff | date = January 8, 2020 | title = Baloxavir marboxil: Synthetic Routes [Five Tabs] | work = Hodoodo.com | location = Morrisville, NC | publisher = MedKoo Biosciences | url = https://hodoodo.com/synthesis/baloxavir-marboxil | accessdate = January 8, 2020 }}</ref>{{better source}}<ref>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).</ref><ref>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).</ref><ref>Shibahara, Setsuya; Fukui, Nobuaki; Maki, Toshikatsu. Polycyclic pyridone derivative, crystal and preparation method thereof. Assignee Shionogi and Co., Ltd., Japan. JP 6212678. (2017).</ref><ref>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).</ref><ref>See also: Zhu, Xiaoyun; Jiang, Weiping. Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug. CN 108440564. (2018).</ref>

⚫
Baloxavir marboxil was approved for sale in Japan in February 2018.<ref>{{cite press release|url=http://www.publicnow.com/view/7E9FBF87835EEBAC31508CC4E1F96D3D77D54C0A|title=Xofluza (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan|date=23 February 2018|via=www.publicnow.com|publisher=[[Shionogi|Shionogi & Co., Ltd.]]}}</ref>{{better source}} 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.<ref name=FDA/> 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.<ref name=FDA/>{{verification needed}} Specifically, the FDA approved the use of Xofluza for people at high risk of developing influenza-related complications.<ref>{{cite press release | title=Genentech Announces FDA Approval of Xofluza (Baloxavir Marboxil) for People at High Risk of Developing Influenza-Related Complications | publisher=[[Genentech]] | via=Business Wire | date=17 October 2019 | url=https://www.businesswire.com/news/home/20191017005525/en | archive-url=https://web.archive.org/web/20191024061608/https://www.businesswire.com/news/home/20191017005525/en | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}}</ref>


==References==
==References==

Revision as of 18:45, 8 January 2020

Baloxavir marboxil
Clinical data
Trade namesXofluza
Other namesS-033188/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 is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day.

It was approved for medical use in the United States in 2018. It was developed by Shionogi Co., a Japanese pharmaceutical company, and Roche AG.[1]

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]

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][5][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.[6][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.[7]

Mechanism of action

Baloxavir marboxil is an influenza therapeutic agent, specifically, an enzyme inhibitor targeting the influenza virus' cap-dependent endonuclease activity,[citation needed] one of the activities of the virus polymerase.[citation needed] 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.[8][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".[8][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.[9][better source needed][10][11][12][13][14]

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.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/
  6. ^ "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.
  7. ^ "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.
  8. ^ 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.
  9. ^ MedKoo Staff (8 January 2020). "Baloxavir marboxil: Synthetic Routes [Five Tabs]". Hodoodo.com. Morrisville, NC: MedKoo Biosciences. Retrieved 8 January 2020.
  10. ^ 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).
  11. ^ 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).
  12. ^ Shibahara, Setsuya; Fukui, Nobuaki; Maki, Toshikatsu. Polycyclic pyridone derivative, crystal and preparation method thereof. Assignee Shionogi and Co., Ltd., Japan. JP 6212678. (2017).
  13. ^ 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).
  14. ^ See also: Zhu, Xiaoyun; Jiang, Weiping. Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug. CN 108440564. (2018).

Further reading

Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Baloxavir_marboxil&oldid=934826792"