Itraconazole

Last updated

Itraconazole
Itraconazole.svg
Clinical data
Trade names Sporanox, Sporaz, Orungal, others
Other namesITZ
AHFS/Drugs.com Monograph
MedlinePlus a692049
License data
Pregnancy
category
Routes of
administration 		By mouth, solution), vaginal suppository, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~55%, maximal if taken with full meal
Protein binding 99.8%
Metabolism Extensive in liver (CYP3A4)
Metabolites Hydroxy-itraconazole, keto-itraconazole,
N-desalkyl-itraconazole [4]
Elimination half-life 21 hours
Excretion Kidney (35%), faeces (54%) [5]
Identifiers
  • (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-rel-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.123.596 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C35H38Cl2N8O4
Molar mass 705.64 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 165 [6]  °C (329 °F)
Solubility in water 7.8 ± 0.4 × 10−6 mol/L (pH 1.6) [6]  mg/mL (20 °C)
  • O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC
  • InChI=1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3/t25?,31-,35-/m0/s1 Yes check.svgY
  • Key:VHVPQPYKVGDNFY-ZPGVKDDISA-N Yes check.svgY
   (verify)

Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. [7] This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. [7] It may be given by mouth or intravenously. [7]

Contents

Common side effects include nausea, diarrhea, abdominal pain, rash, and headache. [7] Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis. [7] It is unclear if use during pregnancy or breastfeeding is safe. [1] It is in the triazole family of medications. [7] It stops fungal growth by affecting the cell membrane or affecting their metabolism. [7]

Itraconazole was patented in 1978 and approved for medical use in the United States in 1992. [7] [8] It is on the World Health Organization's List of Essential Medicines. [9]

Recent research works suggest itraconazole (ITZ) could also be used in the treatment of cancer by inhibiting the hedgehog pathway [10] 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. [11] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis". [12]

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

Itraconazole has been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, glioblastoma and prostate cancer, [13] [14] 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. [15] [16] [17] A recent review 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. [18]

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. [19] The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium. [19] [20]

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". [21] 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: [22]

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

Interactions

The following drugs should not be taken with itraconazole: [23]

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. [25]

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 [26] [27] and angiogenesis. [28] [29] 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, [29] trafficking, [30] and cholesterol biosynthesis pathways. [28] Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity. [31]

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. [32] It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating. [33] [34]

A product (Lozanoc) licensed through the European union decentralised procedure [35] has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.

Chemistry

Chiral centers are marked by asterisks Itraconazole chiral carbons.svg
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). [36] [37]

Four diastereomers of itraconazole Itraconazole enantiomers.svg
Four diastereomers of itraconazole

History

Itraconazole was approved for medical use in the United States in 1992. [38]

It was designated an orphan drug by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). [39] [40] [41] [42] [43]

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References

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  2. ↑ "Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC)". (emc). 1 February 2018. Retrieved 15 May 2020.
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  37. ↑ "Itraconazole on Drugs.com". Drugs.com. Retrieved 28 August 2016.
  38. ↑ "Itraconazole: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 May 2020.
  39. ↑ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 19 May 2016. Retrieved 15 May 2020.
  40. ↑ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 16 August 2016. Retrieved 15 May 2020.
  41. ↑ "Itraconazole Orphan Drug Designation". U.S. Food and Drug Administration (FDA). 30 October 2008. Retrieved 15 May 2020.
  42. ↑ "EU/3/17/1901". European Medicines Agency (EMA). 23 August 2017. Retrieved 15 May 2020.
  43. ↑ "EU/3/18/2024". European Medicines Agency (EMA). 25 May 2018. Retrieved 15 May 2020.
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