Isavuconazonium
{{Short description|Chemical compound}}
{{Use dmy dates|date=September 2021}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
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| image = Isavuconazonium sulfate.svg
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| pronounce =
| tradename = Cresemba
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| DailyMedID = Isavuconazonium
| pregnancy_AU = D
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| routes_of_administration = By mouth, intravenous
| class =
| ATC_prefix = None
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| legal_AU_comment = {{cite web | title=Cresemba isavuconazole (as isavuconazonium sulfate) 200 mg powder for injection vial | website=Therapeutic Goods Administration (TGA) | url=https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305480 | access-date=5 September 2021 | id=ARTG ID 305480 | archive-date=19 June 2022 | archive-url=https://web.archive.org/web/20220619145445/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305480 }}{{cite web | title=Cresemba isavuconazole (as isavuconazonium sulfate) 100 mg capsule blister pack | website=Therapeutic Goods Administration (TGA) | url=https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305452 | access-date=5 September 2021 | id=ARTG ID 305452 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905215438/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=305452 }}{{cite web | title=AusPAR: Isavuconazole (as sulphate) | website=Therapeutic Goods Administration (TGA) | date=22 January 2020 | url=https://www.tga.gov.au/auspar/auspar-isavuconazole-sulphate | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905211807/https://www.tga.gov.au/auspar/auspar-isavuconazole-sulphate | url-status=live }}
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| legal_CA = Rx-only
| legal_CA_comment = {{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00503 | title=Regulatory Decision Summary for Cresemba | website=Drug and Health Product Register | date=23 October 2014 | access-date=7 June 2022 | archive-date=7 June 2022 | archive-url=https://web.archive.org/web/20220607071912/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00503 | url-status=live }}{{cite web | title=Drug and medical device highlights 2018: Helping you maintain and improve your health | website=Health Canada | date=14 October 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html | access-date=17 April 2024 | archive-date=17 April 2024 | archive-url=https://web.archive.org/web/20240417063539/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html | url-status=live }}
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| legal_UK = POM
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| legal_status = Rx-only
| bioavailability =
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| index2_label = sulfate
| CAS_number_Ref =
| CAS_number = 742049-41-8
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| CAS_number2 = 946075-13-4
| CAS_supplemental =
| PubChem = 6918606
| PubChem2 = 72196309
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| ChEBI = 85978
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| ChEMBL_Ref =
| ChEMBL = 1183349
| ChEMBL2 = 3137333
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| synonyms =
| 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_Ref =
| 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
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{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 350800485
| drug_name = Isavuconazole
| image = Isavuconazole structure.svg
| width =
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| image2 = Isavuconazole ball-and-stick model.png
| width2 =
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| caption =
| pronounce =
| tradename =
| Drugs.com =
| MedlinePlus =
| DailyMedID =
| pregnancy_AU = D
| pregnancy_category=
| routes_of_administration = By mouth, intravenous
| class =
| ATC_prefix = J02
| ATC_suffix = AC05
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| legal_BR_comment =
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| legal_US =
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| bioavailability =
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| onset =
| elimination_half-life =
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| excretion =
| CAS_number_Ref =
| CAS_number = 241479-67-4
| CAS_supplemental =
| PubChem = 6918485
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB11633
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| UNII = 60UTO373KE
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D10750
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 85979
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 409153
| NIAID_ChemDB = 416566
| PDB_ligand =
| synonyms = BAL8557
| IUPAC_name = 4-
| 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
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| 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
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| StdInChIKey = DDFOUSQFMYRUQK-RCDICMHDSA-N
| density =
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| solubility = 14.2 ± 0.5 × 10−6 mol/L (pH 7.4)
| sol_units =
| specific_rotation =
}}
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.{{cite web | title=Cresemba- isavuconazonium sulfate capsule; Cresemba- isavuconazonium sulfate injection, powder, lyophilized, for solution | website=DailyMed | date=2 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f7f73b8-586a-4df0-935f-fecd4696c16c | access-date=26 August 2020 | archive-date=30 March 2021 | archive-url=https://web.archive.org/web/20210330214634/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f7f73b8-586a-4df0-935f-fecd4696c16c | url-status=live }}{{cite web | title=Cresemba 100 mg hard capsules - Summary of Product Characteristics (SmPC) | website=(emc) | date=28 June 2021 | url=https://www.medicines.org.uk/emc/product/5071/smpc | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905211752/https://www.medicines.org.uk/emc/product/5071/smpc | url-status=live }}{{cite web | title=Cresemba 200mg Powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=28 June 2021 | url=https://www.medicines.org.uk/emc/medicine/31239 | access-date=5 September 2021 | archive-date=18 June 2017 | archive-url=https://web.archive.org/web/20170618094629/https://www.medicines.org.uk/emc/medicine/31239 | url-status=live }}{{cite journal | vauthors = Donnelley MA, Zhu ES, Thompson GR | title = Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections | journal = Infection and Drug Resistance | volume = 9 | pages = 79–86 | date = 2 June 2016 | pmid = 27330318 | pmc = 4898026 | doi = 10.2147/IDR.S81416 | doi-access = free }} 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.{{cite book | vauthors = Wilkes GM, Barton-Burke M |title=2020-2021 Oncology Nursing Drug Handbook |date=2019 |publisher=Jones & Bartlett Learning |isbn=978-1-284-17132-7 |pages=1874–1876 |url=https://books.google.com/books?id=Biy7DwAAQBAJ&dq=Isavuconazonium&pg=PA1874 }}
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.{{cite journal | vauthors = Miceli MH, Kauffman CA | title = Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent | journal = Clinical Infectious Diseases | volume = 61 | issue = 10 | pages = 1558–65 | date = November 2015 | pmid = 26179012 | doi = 10.1093/cid/civ571 | doi-access = free }}
Contraindications
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.
In preclinical studies, isavuconazonium caused birth defects in animals; it has not been tested in pregnant women.
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.
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.
Pharmacology
After oral or intravenous administration, isavuconazonium is rapidly hydrolysed by esterases in blood or the gastrointestinal tract to the active form, isavuconazole.{{cite journal | vauthors = Pettit NN, Carver PL | title = Isavuconazole: A New Option for the Management of Invasive Fungal Infections | journal = The Annals of Pharmacotherapy | volume = 49 | issue = 7 | pages = 825–42 | date = July 2015 | pmid = 25940222 | doi = 10.1177/1060028015581679 | s2cid = 208875031 }}
Isavuconazole works by inhibition of lanosterol 14α-demethylase, the enzyme responsible for converting lanosterol to ergosterol via a demethylation reaction. The resulting depletion of ergosterol and buildup of lanosterol compromise the fungal cell membrane. Mammalian lanosterol 14α-demethylase is more resistant to inhibition by azoles, making the drug's effects mostly specific to fungi.
Chemistry
Isavuconazonium comprises an N-(3-acetoxypropyl)-N-methylamino-carboxymethyl group linked through an ester moiety to the triazole nitrogen in isavuconazole.{{cite journal|title=Proposed INN: List 96|journal=WHO Drug Information|date=2006|volume=20|issue=4|url=https://www.who.int/medicines/publications/druginformation/innlists/PL96.pdf?ua=1|access-date=5 October 2020|archive-date=5 September 2021|archive-url=https://web.archive.org/web/20210905125231/https://www.who.int/medicines/publications/druginformation/innlists/PL96.pdf?ua=1|url-status=live}}{{cite journal|title=Recommended INN: List 58|journal=WHO Drug Information|date=2007|volume=21|issue=3|url=https://www.who.int/medicines/publications/druginformation/innlists/RL58.pdf?ua=1|access-date=5 October 2020|archive-date=17 September 2020|archive-url=https://web.archive.org/web/20200917105939/https://www.who.int/medicines/publications/druginformation/innlists/RL58.pdf?ua=1|url-status=live}}
In the aquatic media of the body, the isavuconazole molecule is transformed into monohydrate.{{cite journal | vauthors = Voronin AP, Vasilev NA, Surov AO, Churakov AV, Perlovich GL | title = Exploring the solid form landscape of the antifungal drug isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance. | journal = CrystEngComm | date = 2021 | volume = 23 | issue = 48 | pages = 8513–8526 | doi = 10.1039/D1CE01353J | bibcode = 2021CEG....23.8513V | s2cid = 244426797 }}
History
Isavuconazole and isavuconazonium were discovered in Japan by researchers at Roche's research center in Kamakura.{{cite journal | vauthors = Guinea J, Bouza E | title = Isavuconazole: a new and promising antifungal triazole for the treatment of invasive fungal infections | journal = Future Microbiology | volume = 3 | issue = 6 | pages = 603–15 | date = December 2008 | pmid = 19072177 | doi = 10.2217/17460913.3.6.603 }}{{cite journal | vauthors = 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 | title = Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 2 | pages = 191–6 | date = January 2003 | pmid = 12482421 | doi = 10.1016/s0960-894x(02)00892-2 }} 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.{{cite web | title=Isavuconazonium sulfate Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=6 May 2013 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133949 | access-date=26 August 2020 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905125233/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133949 | url-status=live }}{{cite web | title=Isavuconazonium sulfate Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=20 October 2014 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20144478 | access-date=26 August 2020 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905125234/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20144478 | url-status=live }}{{cite web | title=Isavuconazonium sulfate Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=25 October 2013 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133950 | access-date=26 August 2020 | archive-date=5 September 2021 | archive-url=https://web.archive.org/web/20210905125312/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20133950 | url-status=live }}
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.{{cite news|title=Astellas Takes Over Isavuconazole Manufacturing and Promotion in U.S., Canada|url=https://www.genengnews.com/topics/drug-discovery/astellas-takes-over-isavuconazole-manufacturing-and-promotion-in-u-s-canada/|work=Genetic Engineering & Biotechnology News|date=28 February 2014|access-date=21 May 2024|archive-date=5 June 2023|archive-url=https://web.archive.org/web/20230605170119/https://www.genengnews.com/topics/drug-discovery/astellas-takes-over-isavuconazole-manufacturing-and-promotion-in-u-s-canada/|url-status=live}}
The US Food and Drug Administration (FDA) granted approval in March 2015,{{cite web | title=Cresemba Capsules & Cresemba Powder for Injection | website=U.S. Food and Drug Administration (FDA) | date=6 March 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000TOC.cfm | access-date=26 August 2020 | archive-date=1 April 2021 | archive-url=https://web.archive.org/web/20210401001815/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000TOC.cfm | url-status=live }}
- {{lay source |template=cite web |date=2015 |title=207500Orig1s000 / 207501Orig1s000 Labeling |website=Center for Drug Evaluation and Research |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000Lbl.pdf}} and the European Medicines Agency (EMA) approved it in October 2015.{{cite web | title=Cresemba EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cresemba | access-date=26 August 2020 | archive-date=10 August 2020 | archive-url=https://web.archive.org/web/20200810120028/https://www.ema.europa.eu/en/medicines/human/EPAR/cresemba | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
In 2017, Basilea licensed rights to Pfizer to market isavuconazole in Europe and other regions.{{cite news |vauthors=Elvidge S |title=Pfizer builds out anti-infective reach with Basilea deal |url=https://www.biopharmadive.com/news/pfizer-basilea-cresemba-antifungal-europe-marketing-rights/445208/ |work=BioPharma Dive |date=16 June 2017 |access-date=21 May 2024 |archive-date=19 January 2024 |archive-url=https://web.archive.org/web/20240119204310/https://www.biopharmadive.com/news/pfizer-basilea-cresemba-antifungal-europe-marketing-rights/445208/ |url-status=live }}{{cite press release | title=Pfizer Receives Exclusive Commercialization Rights in Europe for Cresemba, a Novel Treatment for Potentially Life-Threatening Fungal Infections Among Immunocompromised Patients | website=Pfizer | date=14 June 2017 | url=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 | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=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 | url-status=live }}{{cite press release | title=Pfizer Enters into Agreement to Develop and Commercialize Cresemba (isavuconazole) in China and Asia Pacific Region | website=Pfizer | date=30 November 2017 | url=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 | access-date=5 September 2021 | archive-date=5 September 2021 | archive-url=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 | url-status=live }}
References
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