Itraconazole

Itraconazole
Names
Trade namesSporanox, Sporaz, Orungal, others
IUPAC name
  • (±)-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
Clinical data
Drug classAntifungal (triazole)[1]
Main usesTinea capitis, histoplasmosis, penicilliosis[2]
Side effectsNausea, diarrhea, abdominal pain, rash, headache[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3[3]
  • US: C (Risk not ruled out)[3]
    Routes of
    use
    By mouth (capsules, solution), local (vaginal suppository), intravenous (IV)
    Defined daily dose200 mg[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa692049
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability~55%, maximal if taken with full meal
    Protein binding99.8%
    MetabolismExtensive in liver (CYP3A4)
    MetabolitesHydroxy-itraconazole, keto-itraconazole,
    N-desalkyl-itraconazole[6]
    Elimination half-life21 hours
    ExcretionUrine (35%), faeces (54%)[7]
    Chemical and physical data
    FormulaC35H38Cl2N8O4
    Molar mass705.64 g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
    SMILES
    • O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC
    InChI
    • 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 checkY
    • Key:VHVPQPYKVGDNFY-ZPGVKDDISA-N checkY

    Itraconazole is an antifungal medication used to treat a number of fungal infections.[1] This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.[1] It may be given by mouth or intravenously.[1]

    Common side effects include nausea, diarrhea, abdominal pain, rash, and headache.[1] Severe side effects may include liver problems, heart failure, Stevens–Johnson syndrome and allergic reactions including anaphylaxis.[1] It is unclear if use during pregnancy or breastfeeding is safe.[3] It is in the triazole family of medications.[1] It stops fungal growth by affecting the cell membrane or affecting their metabolism.[1]

    Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.[1][8] It is on the World Health Organization's List of Essential Medicines.[9] The wholesale cost in the developing world is about US$0.29 per day of treatment as of 2015.[10] In the United States, as of 2021, the wholesale cost of this dose is $2.[11] In the UK, as of 2020, 15 capsules of 100mg itraconazole costs the NHS £3.55.[12]

    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.[13] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".[14]

    It is also prescribed for systemic infections, such as aspergillosis, candidiasis, where other antifungal drugs are inappropriate or ineffective.[15]

    Itraconazole has also recently been explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer.[16] 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.[17][18][19]

    Dosage

    The defined daily dose is 200 mg either by mouth or by injection.[4] For tinea capitis the dose in adults is 200 mg once per day for two to four weeks while the dose is children is 3 to 5 mg/kg daily for 4 weeks.[2] Doses of 200 mg three times per day for three days, followed by 200 mg either one to twice per day for up to 12 weeks may be used for histoplasmosis.[2] The dose is in children is 5 mg/kg.[2] Penicilliosis is treated with 200 mg twice per day for eight weeks.[2]

    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. 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.[20] The tiny blue pellets contained in the capsule are manufactured in Beerse, Belgium.[20][21]

    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".[22] 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 non-diet cola, which may improve absorption in people who have less stomach acid.[23]

    Side effects

    Regrowth following patchy loss associated with itraconazole

    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:[24]

    Side effects that may indicate a greater problem and therefore the need to seek medical attention include:[26]

    Interactions

    The following drugs should not be taken with itraconazole:[27]

    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.[28]

    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 and angiogenesis.[29][30] Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, VEGFR2 phosphorylation, trafficking,[31] and cholesterol biosynthesis pathways.[29] Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.[32]

    Pharmacokinetics

    Itraconazole, 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. It has therefore been conventionally advised that patients take itraconazole after a fatty meal rather than prior to eating.[33]A product (Lozanoc) licensed through the European union decentralised procedure has increased bioavailability, decreased sensitivity to co ingestion of food, and hence decreased variability of serum levels.[34]

    Chemistry

    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 pairs).[35][36][37]

    Four diastereomers of itraconazole

    History

    Itraconazole was patented in 1978 and approved for medical use in the United States in 1992.[1][38] Prior to its development, amphotericin B and ketoconazole were the main drugs for treating systemic fungal infections.[39] In 2016 Itraconazole was designated an orphan drug by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2018.[40][41]

    References

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