Isavuconazonium Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:350800485
Tradename:Cresemba
Dailymedid:Isavuconazonium
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth, intravenous
Atc Prefix:None
Legal Au:S4
Legal Au Comment:[2] [3] [4]
Legal Ca:Rx-only
Legal Ca Comment:[5] [6]
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Status:Rx-only
Index2 Label:sulfate
Cas Number:742049-41-8
Cas Number2:946075-13-4
Pubchem:6918606
Pubchem2:72196309
Drugbank:DB06636
Drugbank2:DBSALT001102
Chemspiderid:5293801
Chemspiderid2:32701987
Unii:VH2L779W8Q
Unii2:31Q44514JV
Kegg:D10644
Kegg2:D10643
Chebi:85978
Chebi2:85977
Chembl:1183349
Chembl2:3137333
Iupac Name:1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-({methyl[3-({[2-(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium
C:35
H:35
F:2
N:8
O:5
S:1
Smiles:[H]C(C)(OC(=O)N(C)C1=C(COC(=O)CNC)C=CC=N1)[N+]1=CN(C[C@](O)(C2=C(F)C=CC(F)=C2)[C@@]([H])(C)C2=NC(=CS2)C2=CC=C(C=C2)C#N)N=C1
Smiles2:OS([O-])(=O)=O.[H]C(C)(OC(=O)N(C)C1=C(COC(=O)CNC)C=CC=N1)[N+]1=CN(C[C@](O)(C2=C(F)C=CC(F)=C2)[C@@]([H])(C)C2=NC(=CS2)C2=CC=C(C=C2)C#N)N=C1
Stdinchi:1S/C35H35F2N8O5S/c1-22(33-42-30(18-51-33)25-9-7-24(15-38)8-10-25)35(48,28-14-27(36)11-12-29(28)37)19-45-21-44(20-41-45)23(2)50-34(47)43(4)32-26(6-5-13-40-32)17-49-31(46)16-39-3/h5-14,18,20-23,39,48H,16-17,19H2,1-4H3/q+1/t22-,23?,35+/m0/s1
Stdinchi2:1S/C35H35F2N8O5S.H2O4S/c1-22(33-42-30(18-51-33)25-9-7-24(15-38)8-10-25)35(48,28-14-27(36)11-12-29(28)37)19-45-21-44(20-41-45)23(2)50-34(47)43(4)32-26(6-5-13-40-32)17-49-31(46)16-39-3;1-5(2,3)4/h5-14,18,20-23,39,48H,16-17,19H2,1-4H3;(H2,1,2,3,4)/q+1;/p-1/t22-,23?,35+;/m0./s1
Stdinchikey:RSWOJTICKMKTER-QXLBVTBOSA-N
Stdinchikey2:LWXUIUUOMSMZKJ-KLFWAVJMSA-M
Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:350800485
Drug Name:Isavuconazole
Pregnancy Au:D
Routes Of Administration:By mouth, intravenous
Atc Prefix:J02
Atc Suffix:AC05
Cas Number:241479-67-4
Pubchem:6918485
Drugbank:DB11633
Chemspiderid:5293682
Unii:60UTO373KE
Kegg:D10750
Chebi:85979
Chembl:409153
Niaid Chemdb:416566
Synonyms:BAL8557
Iupac Name:4-benzonitrile
C:22
H:17
F:2
N:5
O:1
S:1
Smiles:C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Stdinchi:1S/C22H17F2N5OS/c1-14(21-28-20(10-31-21)16-4-2-15(9-25)3-5-16)22(30,11-29-13-26-12-27-29)18-8-17(23)6-7-19(18)24/h2-8,10,12-14,30H,11H2,1H3/t14-,22+/m0/s1
Stdinchikey:DDFOUSQFMYRUQK-RCDICMHDSA-N
Melting Point:122
Solubility:14.2 ± 0.5 × 10−6 mol/L (pH 7.4)

Isavuconazonium, sold under the brand name Cresemba, is a systemic antifungal medication of the triazole class which is used to treat invasive aspergillosis and mucormycosis.[7] [8] [9] [10] It is used as the sulfate. It is taken by mouth or given via injection into a vein.

The most common side effects include abnormal liver tests, nausea, vomiting, difficulty breathing, abdominal pain, diarrhea, injection site reactions, headache, low blood potassium and skin rash.

Isavuconazonium is a prodrug of isavuconazole.[11]

Medical uses

Isavuconazonium is used to treat invasive aspergillosis and invasive mucormycosis in adults aged eighteen years old and older. It is available in a capsule for administration by mouth and as a powder for administration via infusion.[7] [8] [9] [10] [12]

Contraindications

Isavuconazonium is contraindicated in people taking strong CYP3A4 inhibitors, strong CYP3A4 inducers, or moderate CYP3A4 or CYP3A5 inducers.[8] [9] [7] It is contraindicated in people with familial short QT syndrome.[8] [9] [7]

Side effects

Common adverse effects (occurring in between 1 and 10% of people) include low potassium, decreased appetite, delirium, headache, sleepiness, vein inflammation, difficulty breathing, acute respiratory failure, vomiting, diarrhea, nausea, stomach pain, elevated results in liver function tests, rash, itchy skin, kidney failure, chest pain, and fatigue. There are several uncommon side effects as well.[8] [9]

In preclinical studies, isavuconazonium caused birth defects in animals; it has not been tested in pregnant women.[8] [9] [7]

Interactions

Isavuconazonium is converted into isavuconazole inside the body, and isavuconazole is a substrate for CYP3A4 or CYP3A5. Many other medications inhibit or induce those two enzymes, and isavuconazonium should not be administered with them. Inducers result in levels of isavuconazole that are too low and won't work, and inhibitors can cause high levels of isavuconazole which will in turn cause increased adverse events and toxicity. Likewise isavuconazonium can interfere with appropriate dosing of other drugs that are substrates for those enzymes.[8] [9]

In addition, isavuconazole induces CYP2B6 and can decrease the amount of drugs that are metabolized by the enzyme. Isavuconazole inhibits P-glycoprotein (P-gp), BCRP, SLC22A2, and uridine diphosphate-glucuronosyltransferases, each of which remove drugs from circulation; isavuconazonium will increase the amount of drugs that are affected by those proteins and may increase their toxicities.[8] [9]

Pharmacology

After oral or intravenous administration, isavuconazonium is rapidly hydrolysed by esterases in blood or the gastrointestinal tract to the active form, isavuconazole.[8] [9] [13]

Isavuconazole works by inhibition of lanosterol 14α-demethylase, the enzyme responsible for converting lanosterol to ergosterol by demethylation. The resulting depletion of ergosterol and buildup of lanosterol compromise the structure of the fungal cell membrane. Mammalian cells are resistant to demethylation inhibition by azoles, making the drug effects specific to fungi.[8] [9] [13]

Chemistry

Isavuconazonium comprises an N-(3-acetoxypropyl)-N-methylamino-carboxymethyl group linked through an ester moiety to the triazole nitrogen in isavuconazole.[14] [15] In the aquatic media of the body, the isavuconazole molecule is transformed into monohydrate.[16]

History

Isavuconazole and isavuconazonium were discovered in Japan by researchers at Roche's research center in Kamakura.[17] [18] Basilea Pharmaceutica, which had been spun out of Roche to develop antimicrobial assets, developed isavuconazonium through Phase II clinical trials. In February 2010, Basilea partnered with Astellas Pharma to complete Phase III trials, obtain regulatory approvals, and market the drug. In 2013 and 2014, the partners won orphan drug designation in the US for isavuconazonium for treating invasive aspergillosis, mucormycosis, and invasive candidiasis.[13] [19] [20] [21]

In 2014, Basilea and Astellas amended the agreement to give Astellas sole marketing authority in North America, and Basilea the rights to market in the rest of the world.[22]

The US Food and Drug Administration (FDA) granted approval in March 2015,[13] [23] and the European Medicines Agency (EMA) approved it in October 2015.[24] [8] [9]

In 2017, Basilea licensed rights to Pfizer to market isavuconazole in Europe and other regions.[25] [26] [27]

Notes and References

  1. Web site: Isavuconazonium (Cresemba) Use During Pregnancy . Drugs.com . 31 January 2020 . 26 August 2020 . 2 December 2020 . https://web.archive.org/web/20201202231745/https://www.drugs.com/pregnancy/isavuconazonium.html . live .
  2. Web site: Cresemba isavuconazole (as isavuconazonium sulfate) 200 mg powder for injection vial . Therapeutic Goods Administration (TGA) . 5 September 2021 . ARTG ID 305480 . 19 June 2022 . https://web.archive.org/web/20220619145445/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305480 .
  3. Web site: Cresemba isavuconazole (as isavuconazonium sulfate) 100 mg capsule blister pack . Therapeutic Goods Administration (TGA) . 5 September 2021 . ARTG ID 305452 . 5 September 2021 . https://web.archive.org/web/20210905215438/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305452 .
  4. Web site: AusPAR: Isavuconazole (as sulphate) . Therapeutic Goods Administration (TGA) . 22 January 2020 . 5 September 2021 . 5 September 2021 . https://web.archive.org/web/20210905211807/https://www.tga.gov.au/auspar/auspar-isavuconazole-sulphate . live .
  5. Web site: Regulatory Decision Summary for Cresemba . Drug and Health Product Register . 23 October 2014 . 7 June 2022 . 7 June 2022 . https://web.archive.org/web/20220607071912/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00503 . live .
  6. Web site: Drug and medical device highlights 2018: Helping you maintain and improve your health . . 14 October 2020 . 17 April 2024 . 17 April 2024 . https://web.archive.org/web/20240417063539/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html . live .
  7. Web site: Cresemba- isavuconazonium sulfate capsule; Cresemba- isavuconazonium sulfate injection, powder, lyophilized, for solution . DailyMed . 2 December 2019 . 26 August 2020 . 30 March 2021 . https://web.archive.org/web/20210330214634/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f7f73b8-586a-4df0-935f-fecd4696c16c . live .
  8. Web site: Cresemba 100 mg hard capsules - Summary of Product Characteristics (SmPC) . (emc) . 28 June 2021 . 5 September 2021 . 5 September 2021 . https://web.archive.org/web/20210905211752/https://www.medicines.org.uk/emc/product/5071/smpc . live .
  9. Web site: Cresemba 200mg Powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) . (emc) . 28 June 2021 . 5 September 2021 . 18 June 2017 . https://web.archive.org/web/20170618094629/https://www.medicines.org.uk/emc/medicine/31239 . live .
  10. Donnelley MA, Zhu ES, Thompson GR . Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections . Infection and Drug Resistance . 9 . 79–86 . 2 June 2016 . 27330318 . 4898026 . 10.2147/IDR.S81416 . free .
  11. Book: Wilkes GM, Barton-Burke M . 2020-2021 Oncology Nursing Drug Handbook . 2019 . Jones & Bartlett Learning . 978-1-284-17132-7 . 1874–1876 .
  12. Miceli MH, Kauffman CA . Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent . Clinical Infectious Diseases . 61 . 10 . 1558–65 . November 2015 . 26179012 . 10.1093/cid/civ571 . free .
  13. Pettit NN, Carver PL . Isavuconazole: A New Option for the Management of Invasive Fungal Infections . The Annals of Pharmacotherapy . 49 . 7 . 825–42 . July 2015 . 25940222 . 10.1177/1060028015581679 . 208875031 .
  14. Proposed INN: List 96. WHO Drug Information. 2006. 20. 4. 5 October 2020. 5 September 2021. https://web.archive.org/web/20210905125231/https://www.who.int/medicines/publications/druginformation/innlists/PL96.pdf?ua=1. live.
  15. Recommended INN: List 58. WHO Drug Information. 2007. 21. 3. 5 October 2020. 17 September 2020. https://web.archive.org/web/20200917105939/https://www.who.int/medicines/publications/druginformation/innlists/RL58.pdf?ua=1. live.
  16. Voronin AP, Vasilev NA, Surov AO, Churakov AV, Perlovich GL . Exploring the solid form landscape of the antifungal drug isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance. . CrystEngComm . 2021 . 23 . 48 . 8513–8526 . 10.1039/D1CE01353J . 244426797 .
  17. Guinea J, Bouza E . Isavuconazole: a new and promising antifungal triazole for the treatment of invasive fungal infections . Future Microbiology . 3 . 6 . 603–15 . December 2008 . 19072177 . 10.2217/17460913.3.6.603 .
  18. Ohwada J, Tsukazaki M, Hayase T, Oikawa N, Isshiki Y, Fukuda H, Mizuguchi E, Sakaitani M, Shiratori Y, Yamazaki T, Ichihara S, Umeda I, Shimma N . Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole . Bioorganic & Medicinal Chemistry Letters . 13 . 2 . 191–6 . January 2003 . 12482421 . 10.1016/s0960-894x(02)00892-2 .
  19. Web site: Isavuconazonium sulfate Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 6 May 2013 . 26 August 2020 . 5 September 2021 . https://web.archive.org/web/20210905125233/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133949 . live .
  20. Web site: Isavuconazonium sulfate Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 20 October 2014 . 26 August 2020 . 5 September 2021 . https://web.archive.org/web/20210905125234/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20144478 . live .
  21. Web site: Isavuconazonium sulfate Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 25 October 2013 . 26 August 2020 . 5 September 2021 . https://web.archive.org/web/20210905125312/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133950 . live .
  22. News: Astellas Takes Over Isavuconazole Manufacturing and Promotion in U.S., Canada. Genetic Engineering & Biotechnology News. 28 February 2014. 21 May 2024. 5 June 2023. https://web.archive.org/web/20230605170119/https://www.genengnews.com/topics/drug-discovery/astellas-takes-over-isavuconazole-manufacturing-and-promotion-in-u-s-canada/. live.
  23. Web site: Cresemba Capsules & Cresemba Powder for Injection . U.S. Food and Drug Administration (FDA) . 6 March 2015 . 26 August 2020 . 1 April 2021 . https://web.archive.org/web/20210401001815/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000TOC.cfm . live .
  24. Web site: Cresemba EPAR . European Medicines Agency (EMA) . 17 September 2018 . 26 August 2020 . 10 August 2020 . https://web.archive.org/web/20200810120028/https://www.ema.europa.eu/en/medicines/human/EPAR/cresemba . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  25. News: Elvidge S . Pfizer builds out anti-infective reach with Basilea deal . BioPharma Dive . 16 June 2017 . 21 May 2024 . 19 January 2024 . https://web.archive.org/web/20240119204310/https://www.biopharmadive.com/news/pfizer-basilea-cresemba-antifungal-europe-marketing-rights/445208/ . live .
  26. Pfizer Receives Exclusive Commercialization Rights in Europe for Cresemba, a Novel Treatment for Potentially Life-Threatening Fungal Infections Among Immunocompromised Patients . Pfizer . 14 June 2017 . 5 September 2021 . 5 September 2021 . https://web.archive.org/web/20210905211752/https://www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_exclusive_commercialization_rights_in_europe_for_cresemba_a_novel_treatment_for_potentially_life_threatening_fungal_infections_among_immunocompromised_patients . live .
  27. Pfizer Enters into Agreement to Develop and Commercialize Cresemba (isavuconazole) in China and Asia Pacific Region . Pfizer . 30 November 2017 . 5 September 2021 . 5 September 2021 . https://web.archive.org/web/20210905211752/https://www.pfizer.com/news/press-release/press-release-detail/pfizer_enters_into_agreement_to_develop_and_commercialize_cresemba_isavuconazole_in_china_and_asia_pacific_region . live .

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