Chemistry:Itraconazole

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Short description: Chemical compound used as medication to treat fungal infections
Itraconazole
Itraconazole.svg
Clinical data
Trade namesSporanox, Sporaz, Orungal, others
Other namesITZ
AHFS/Drugs.comMonograph
MedlinePlusa692049
License data
Pregnancy
category
  • AU: B3[1]
  • US: C (Risk not ruled out)[1]
Routes of
administration		By mouth (capsules, solution), local (vaginal suppository), intravenous (IV)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~55%, maximal if taken with full meal
Protein binding99.8%
MetabolismExtensive in liver (CYP3A4)
MetabolitesHydroxy-itraconazole, keto-itraconazole,
N-desalkyl-itraconazole[3]
Elimination half-life21 hours
ExcretionUrine (35%), faeces (54%)[4]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC35H38Cl2N8O4
Molar mass705.64 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point165[5] °C (329 °F)
Solubility in water7.8 ± 0.4 × 10−6 mol/L (pH 1.6)[5] mg/mL (20 °C)
  (verify)

Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections.[6] This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.[6] It may be given by mouth or intravenously.[6]

Common side effects include nausea, diarrhea, abdominal pain, rash, and headache.[6] Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis.[6] It is unclear if use during pregnancy or breastfeeding is safe.[1] It is in the triazole family of medications.[6] It stops fungal growth by affecting the cell membrane or affecting their metabolism.[6]

Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.[6][7] It is on the World Health Organization's List of Essential Medicines.[8]

Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway[9] in a similar way to sonidegib.

Medical uses

Itraconazole has a broader spectrum of activity than fluconazole (but not as broad as voriconazole or posaconazole). In particular, it is active against Aspergillus, which fluconazole is not. It is also licensed for use in blastomycosis, sporotrichosis, histoplasmosis, and onychomycosis. Itraconazole is over 99% protein-bound and has virtually no penetration into cerebrospinal fluid. Therefore, it should not be used to treat meningitis or other central nervous system infections.[10] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".[11]

It is also prescribed for systemic infections, such as aspergillosis, candidiasis, and cryptococcosis, where other antifungal drugs are inappropriate or ineffective.[citation needed]

In the past decade, itraconazole has been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer.[12] For example, in a phase II study involving men with advanced prostate cancer, high-dose itraconazole (600 mg/day) was associated with significant PSA responses and a delay in tumor progression. Itraconazole also showed activity in a phase II trial in men with non-small cell lung cancer when it was combined with the chemotherapy agent, pemetrexed.[13][14][15] A recent review has also highlights its use topically and orally in conjunction with other chemotherapeutic agents for advanced and metastatic basal cell carcinomas that cannot be treated surgically.[16]

Available forms

Itraconazole is produced as blue 22 mm (0.87 in) capsules with tiny 1.5 mm (0.059 in) blue pellets inside. Each capsule contains 100 mg and is usually taken twice a day at twelve-hour intervals. The Sporanox brand of itraconazole has been developed and marketed by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson.[citation needed] The three-layer structure of these blue capsules is complex because itraconazole is insoluble and is sensitive to pH. The complicated procedure not only requires a specialized machine to create it, but also the method used has manufacturing problems. Also, the pill is quite large, making it difficult for many patients to swallow. Parts of the processes of creating Sporanox were discovered by the Korean Patent Laid-open No. 10-2001-2590.[17] The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium.[17][18]

The oral solution is better absorbed. The cyclodextrin contained in the oral solution can cause an osmotic diarrhea, and if this is a problem, then half the dose can be given as oral solution and half as capsule to reduce the amount of cyclodextrin given.[citation needed] "Sporanox" itraconazole capsules should always be taken with food, as this improves absorption, however the manufacturers of "Lozanoc" assert that it may be taken "without regard to meals".[19] Itraconazole oral solution should be taken an hour before food, or two hours after food (and likewise if a combination of capsules and oral solution are used). Itraconazole may be taken with orange juice or cola, as absorption is also improved by acid. Absorption of itraconazole is impaired when taken with an antacid, H2 blocker or proton pump inhibitor.[citation needed]

Side effects

Itraconazole is a relatively well-tolerated drug (although not as well tolerated as fluconazole or voriconazole) and the range of adverse effects it produces is similar to the other azole antifungals:[20]

  • elevated alanine aminotransferase levels are found in 4% of people taking itraconazole
  • "small but real risk" of developing congestive heart failure[20]
  • liver failure, sometimes fatal

The cyclodextrin used to make the syrup preparation can cause diarrhea. Side effects that may indicate a greater problem include:[citation needed]


  • nausea
  • vomiting
  • abdominal pain
  • fatigue
  • loss of appetite
  • yellow skin (jaundice)
  • yellow eyes
  • itching
  • dark urine
  • pale stool
  • headache


Interactions

The following drugs should not be taken with itraconazole:[21]



Pharmacology

Pharmacodynamics

The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal-mediated synthesis of ergosterol, via inhibition of lanosterol 14α-demethylase. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications.[23]

Itraconazole is pharmacologically distinct from other azole antifungal agents in that it is the only inhibitor in this class that has been shown to inhibit both the hedgehog signaling pathway[24][25] and angiogenesis.[26][27] These distinct activities are unrelated to inhibition of the cytochrome P450 lanosterol 14 alpha-demethylase and the exact molecular targets responsible remain unidentified. Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, VEGFR2 phosphorylation,[27] trafficking,[28] and cholesterol biosynthesis pathways.[26] Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.[29]

Pharmacokinetics

Itraconazole, like cyclosporine, quinidine, and clarithromycin, can inhibit P-glycoprotein, causing drug interactions by reducing elimination and increasing absorption of organic cation drugs. With conventional itraconazole preparations serum levels can vary greatly between patients, often resulting in serum concentrations lower than the therapeutic index.[30] It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating.[31][32]

A product (Lozanoc) licensed through the European union decentralised procedure[33] has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.

Chemistry

Chiral centers are marked by asterisks

The itraconazole molecule has three chiral carbons. The two chiral centers in the dioxolane ring are fixed in relation to one another, and the triazolomethylene and aryloxymethylene dioxolane-ring substituents are always cis to each other. The clinical formulation is a 1:1:1:1 mixture of four stereoisomers (two enantiomeric pairs).[34][35]

Four diastereomers of itraconazole

History

Itraconazole was approved for medical use in the United States in 1992.[36]

It was designated an orphan drug by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[37][38][39][40][41]

References

  1. ↑ 1.0 1.1 1.2 "Itraconazole Use During Pregnancy". 20 March 2019. https://www.drugs.com/pregnancy/itraconazole.html. 
  2. ↑ "Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC)". 1 February 2018. https://www.medicines.org.uk/emc/product/1522/smpc. 
  3. ↑ "Role of itraconazole metabolites in CYP3A4 inhibition". Drug Metabolism and Disposition 32 (10): 1121–1131. October 2004. doi:10.1124/dmd.104.000315. PMID 15242978. 
  4. ↑ "Sporanox (itraconazole) Capsules. Full Prescribing Information". Janssen Pharmaceuticals, Inc.. http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/pi-sporanoxcapsules.pdf. 
  5. ↑ 5.0 5.1 "Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility". International Journal of Pharmaceutics 599: 120441. April 2021. doi:10.1016/j.ijpharm.2021.120441. PMID 33675927. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Itraconazole". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/itraconazole.html. 
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 503. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA503. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole". OncoTargets and Therapy 12: 6875–6886. 2019. doi:10.2147/OTT.S223119. PMID 31692536. 
  10. ↑ The Sanford Guide to antimicrobial therapy. Antimicrobial Therapy, Incorporated. 2006. ISBN 978-1-930808-30-0. https://archive.org/details/sanfordguidetoan00davi. [page needed]
  11. ↑ "Itraconazole". Johns Hopkins. 2007-07-24. http://www.hopkins-abxguide.org/terminals/antibiotics_more.cfm?id=81&fc=p. 
  12. ↑ "Search results for Itraconazole". ClinicalTrials.gov. U.S. National Institutes of Health. http://clinicaltrials.gov/ct2/results?term=itraconazole. 
  13. ↑ "Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer". Cancer Research 71 (21): 6764–6772. 2011. doi:10.1158/0008-5472.CAN-11-0691. PMID 21896639. 
  14. ↑ "Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer". The Oncologist 18 (2): 163–173. 2013. doi:10.1634/theoncologist.2012-314. PMID 23340005. 
  15. ↑ "Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer". Journal of Thoracic Oncology 8 (5): 619–623. May 2013. doi:10.1097/JTO.0b013e31828c3950. PMID 23546045. 
  16. ↑ "Itraconazole in the treatment of basal cell carcinoma: A case-based review of the literature". Australasian Journal of Dermatology 62 (3): 394–397. 2021. doi:10.1111/ajd.13655. PMID 34160824. 
  17. ↑ 17.0 17.1 Lee KH, Park ES, Chi SC, "Composition comprising Itraconazole for oral administration", US patent 20050226924, published 13 October 2005, assigned to FDL Inc.
  18. ↑ "Sporanox (Itraconazole Capsules)". Janssen. June 2006. http://www.sporanox.com/active/janus/en_US/assets/common/company/pi/sporanox.pdf. 
  19. ↑ "SUBA Bioavailability Technology". Mayne Pharma Group. http://maynepharma.com/drug-delivery/suba-bioavailability-technology/suba-bioavailability-technology. 
  20. ↑ 20.0 20.1 "The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis". FDA Public Health Advisory. May 9, 2001. https://www.fda.gov/CDER/drug/advisory/sporanox-lamisil/advisory.htm. 
  21. ↑ "Sporanox (Itraconazole) Capsules". Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research. U.S. Food and Drug Administration (FDA). https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303524.htm. 
  22. ↑ "Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report". Journal of Medical Case Reports 5: 333. July 2011. doi:10.1186/1752-1947-5-333. PMID 21801420. 
  23. ↑ Katzung & Trevor's Pharmacology: Examination & Board Review (Eleventh ed.). New York: McGraw Hill Medical. 2015. pp. 397. ISBN 978-0-07-182635-8. 
  24. ↑ "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth". Cancer Cell 17 (4): 388–99. 2010. doi:10.1016/j.ccr.2010.02.027. PMID 20385363. 
  25. ↑ "Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists". Cancer Cell 23 (1): 23–34. 2013. doi:10.1016/j.ccr.2012.11.017. PMID 23291299. 
  26. ↑ 26.0 26.1 "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole". ACS Chemical Biology 2 (4): 263–70. 2007. doi:10.1021/cb600362d. PMID 17432820. 
  27. ↑ 27.0 27.1 "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer". Cancer Research 71 (21): 6764–72. 2011. doi:10.1158/0008-5472.CAN-11-0691. PMID 21896639. 
  28. ↑ "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences 107 (10): 4764–9. 2010. doi:10.1073/pnas.0910872107. PMID 20176935. Bibcode: 2010PNAS..107.4764X. 
  29. ↑ "Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling". Journal of Medicinal Chemistry 54 (20): 7363–74. 2011. doi:10.1021/jm200944b. PMID 21936514. 
  30. ↑ "Systemic availability of itraconazole in lung transplantation". Antimicrob. Agents Chemother. 40 (9): 2217–20. 1996. doi:10.1128/AAC.40.9.2217. PMID 8878612. 
  31. ↑ "[Influence of foods on the absorption of antimicrobial agents]" (in es). Nutr Hosp 12 (6): 277–88. 1997. PMID 9477653. 
  32. ↑ "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers". Antimicrob. Agents Chemother. 37 (4): 778–84. 1993. doi:10.1128/aac.37.4.778. PMID 8388198. 
  33. ↑ "Lozanoc 50 Mg Hard Capsules (Itraconazole)". Public Assessment Report Decentralised Procedure. UK Medicines and Health Care Products Regulatory Agency. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con249676.pdf. 
  34. ↑ "Stereochemical aspects of itraconazole metabolism in vitro and in vivo". Drug Metabolism and Disposition 34 (4): 583–590. April 2006. doi:10.1124/dmd.105.008508. PMID 16415110. 
  35. ↑ "Itraconazole on Drugs.com". https://www.drugs.com/pro/itraconazole.html. 
  36. ↑ "Itraconazole: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020083. 
  37. ↑ "Itraconazole Orphan Drug Designation". 19 May 2016. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=473715. 
  38. ↑ "Itraconazole Orphan Drug Designation". 16 August 2016. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=509515. 
  39. ↑ "Itraconazole Orphan Drug Designation". 30 October 2008. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=257308. 
  40. ↑ "EU/3/17/1901". 23 August 2017. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3171901. 
  41. ↑ "EU/3/18/2024". 25 May 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182024. 

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