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Itraconazole

itraconazole, itraconazole 100mg
Itraconazole, invented in 1984, is a triazole antifungal agent for fungal infections The drug may be given by mouth or intravenously

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system3

Contents

  • 1 Medical uses
    • 11 Available forms
  • 2 Adverse effects
    • 21 Interactions
  • 3 Mechanism of action
  • 4 Pharmacokinetics
  • 5 Anti-cancer properties
  • 6 Chemistry
  • 7 See also
  • 8 Footnotes
  • 9 External links

Medical usesedit

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 never be used to treat meningitis or other central nervous system infections4 According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis"5

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

Itraconazole has also recently been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer6 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, pemetrexed789

Available formsedit

Itraconazole is produced as blue 22 mm 087 in capsules with tiny 15 mm 0059 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 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 10-2001-259010 The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium1011

The intravenous preparation is no longer available in the US as of October 11, 2007 per Ortho-Biotech Professional Letter but may be available in other countries

Conventional itraconazole eg Sporanox has relatively low bioavailability after oral administration, especially when given in capsule form on an empty stomach The capsule form is a molecular dispersion of itraconazole in amorphous HPMC polymer The fast-dissolving polymer targets a supersaturated solution of itraconazole from which enhanced absorption can be expected Recently, itraconazole was found to contribute to the formation of nanofibers in certain simulated intestinal fluids These nanofibers have a uniform width of 12 nm and a length up to several micrometers12 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 "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"13 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 inhibitorcitation needed

Adverse effectsedit

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:14

  • elevated alanine aminotransferase levels are found in 4% of people taking itraconazole
  • "small but real risk" of developing congestive heart failure14
  • liver failure, sometimes fatal

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

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

Interactionsedit

The following drugs should not be taken with itraconazole:15

  • amiodarone Cordarone;16
  • cisapride
  • dofetilide
  • nisoldipine
  • pimozide
  • quinidine
  • lurasidone
  • lovastatin or simvastatin
  • midazolam or triazolam
  • ergot medicines such as
    • dihydroergotamine
    • ergometrine
    • ergotamine
    • methylergonovine

Mechanism of actionedit

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 medications17

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 pathway1819 and angiogenesis2021 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,21 trafficking,22 and cholesterol biosynthesis pathways20 Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity23

Pharmacokineticsedit

Itraconazole, like cyclosporine, quinidine and clarithromycin, can inhibit P-glycoproteins causing drug-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 index24 It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating2526

A product Lozanoc licensed through the European union decentralised procedure27 has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels

Anti-cancer propertiesedit

Itraconazole has been investigated as an anti-cancer agent28 A small randomized clinical trial found that patient survival was increased when itraconazole was added to pemetrexed Median survival for the patients in the study who received both itraconazole and pemetrexed was 32 months, while median survival for patients who only received pemetrexed was 8 months29

Chemistryedit

Chiral centers are marked by asterisks

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 pairs3031

Four diastereomers of itraconazole

See alsoedit

  • Fluconazole
  • Lanosterol 14α-demethylase

Footnotesedit

  1. ^ Isoherranen, N; Kunze, KL; Allen, KE; Nelson, WL; Thummel, KE October 2004 "Role of Itraconazole Metabolites in CYP3A4 Inhibition" PDF Drug Metabolism and Disposition: the Biological Fate of Chemicals 32 10: 1121–31 PMID 15242978 doi:101124/dmd104000315 Retrieved 28 August 2016 
  2. ^ "Sporanox itraconazole Capsules Full Prescribing Information" PDF Janssen Pharmaceuticals, Inc Retrieved 28 August 2016 
  3. ^ "WHO Model List of Essential Medicines 20th List" PDF World Health Organization March 2017 Retrieved 29 June 2017 
  4. ^ Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA 2006 The Sanford Guide to antimicrobial therapy ISBN 1-930808-30-5 CS1 maint: Multiple names: authors list linkpage needed
  5. ^ Pham, P; Bartlett, JG 2007-07-24 "Itraconazole" Johns Hopkins 
  6. ^ "Search results for Itraconazole" ClinicalTrialsgov US National Institutes of Health 
  7. ^ Aftab BT, Dobromilskaya I, Liu JO, Rudin CM "Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer" PDF Cancer Research 71 21: 6764–6772 PMC 3206167  PMID 21896639 doi:101158/0008-5472CAN-11-0691 
  8. ^ Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, King S, Frost A, Ajiboye AS, Zhao M, Mendonca J, Kachhap SK, Rudek MA, Carducci MA 2013 "Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer" PDF The Oncologist 18 2: 163–173 PMC 3579600  PMID 23340005 doi:101634/theoncologist2012-314 
  9. ^ Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P, Liu JO May 2013 "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 PMC 3636564  PMID 23546045 doi:101097/JTO0b013e31828c3950 
  10. ^ a b Composition comprising Itraconazole for oral administration 2004 Fresh Patentscom 26 October 2006
  11. ^ Sporanox Itraconazole Capsules June 2006 Janssen 26 October 2006
  12. ^ Mellaerts R, Aerts A, Caremans TP, Vermant J, Van den Mooter G, Martens JA, Augustijns P 2010 "Growth of Itraconazole Nanofibers in Supersaturated Simulated Intestinal Fluid" Molecular Pharmaceutics 7 3: 905–13 PMID 20232903 doi:101021/mp900300j 
  13. ^ "SUBA™ Bioavailability Technology" Mayne Pharma Group 
  14. ^ a b "The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis" FDA Public Health Advisory May 9, 2001 Archived from the original on 2009-05-28 Retrieved 2006-08-10 
  15. ^ "Sporanox Itraconazole Capsules" Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research United States Food and Drug Administration 
  16. ^ "Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report" 
  17. ^ Katzung & Trevor's 2015 Pharmacology Examination & Board Review McGraw Hill p 397 
  18. ^ Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA 2010 "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth" Cancer Cell 17 4: 388–99 PMID 20385363 doi:101016/jccr201002027 
  19. ^ Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH, Beachy PA, Rudin CM 2013 "Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists" Cancer Cell 23 1: 23–34 PMC 3548977  PMID 23291299 doi:101016/jccr201211017 
  20. ^ a b Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO 2007 "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole" ACS Chemical Biology 2 4: 263–70 PMID 17432820 doi:101021/cb600362d 
  21. ^ a b Aftab BT, Dobromilskaya I, Liu JO, Rudin CM 2011 "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer" Cancer Research 71 21: 6764–72 PMC 3206167  PMID 21896639 doi:101158/0008-5472CAN-11-0691 
  22. ^ Xu J, Dang Y, Ren YR, Liu JO 2010 "Cholesterol trafficking is required for mTOR activation in endothelial cells" Proceedings of the National Academy of Sciences 107 10: 4764–9 PMC 2842052  PMID 20176935 doi:101073/pnas0910872107 
  23. ^ Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO 2011 "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 PMC 3307530  PMID 21936514 doi:101021/jm200944b 
  24. ^ Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, Miller OL, Calhoon JH, Rinaldi MG 1996 "Systemic availability of itraconazole in lung transplantation" Antimicrob Agents Chemother 40 9: 2217–20 PMC 163504  PMID 8878612 
  25. ^ Fraga Fuentes MD, García Díaz B, de Juana Velasco P, Bermejo Vicedo MT 1997 "Influence of foods on the absorption of antimicrobial agents" Nutr Hosp in Spanish 12 6: 277–88 PMID 9477653 
  26. ^ Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V 1993 "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers" Antimicrob Agents Chemother 37 4: 778–84 PMC 187759  PMID 8388198 doi:101128/aac374778 
  27. ^ "Lozanoc 50 Mg Hard Capsules Itraconazole" PDF Public Assessment Report Decentralised Procedure UK Medicines and Health Care Products Regulatory Agency 
  28. ^ Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P 2015-04-15 "Repurposing Drugs in Oncology ReDO—itraconazole as an anti-cancer agent" ecancermedicalscience 9 ISSN 1754-6605 PMC 4406527  PMID 25932045 doi:103332/ecancer2015521 
  29. ^ Rudin, Charles M; Brahmer, Julie R; Juergens, Rosalyn A; Hann, Christine L; Ettinger, David S; Sebree, Rosa; Smith, Ruth; Aftab, Blake T; Huang, Peng 2013-05-01 "Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for Metastatic Non-Squamous Non-Small Cell Lung Cancer" Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 8 5: 619–623 ISSN 1556-0864 PMC 3636564  PMID 23546045 doi:101097/JTO0b013e31828c3950 
  30. ^ Kunze, KL; Nelson, WL; Kharasch, ED; Thummel, KE; Isoherranen, N April 2006 "Stereochemical Aspects of Itraconazole Metabolism in vitro and in vivo" PDF Drug Metabolism and Disposition: the Biological Fate of Chemicals 34 4: 583–90 PMID 16415110 doi:101124/dmd105008508 Retrieved 28 August 2016 
  31. ^ "Itraconazole on Drugscom" Drugscom Retrieved 28 August 2016 

External linksedit

  • General pharmacologic information about itraconazole, National Institutes of Health
  • Itraconazole Oral Route, Mayo Clinic

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