Monograph of Itraconazole

Introduction and Overview

Itraconazole, a triazole antifungal agent, has been widely employed in the treatment of invasive and superficial fungal infections since its introduction in the late 1980s. Its broad spectrum of activity against dermatophytes, yeasts, and molds, coupled with a favorable safety profile in many patient populations, has positioned itraconazole as a cornerstone in antifungal pharmacotherapy. The drug’s unique pharmacokinetic characteristics, particularly its high lipophilicity and extensive enterohepatic recirculation, render it distinct among azoles, thereby influencing dosing strategies and clinical outcomes. A comprehensive understanding of itraconazole is essential for clinicians and pharmacists, as its therapeutic window is narrow and its interaction potential significant.

Learning Objectives

• Explain the classification and chemical properties of itraconazole.
• Describe the pharmacodynamic mechanisms that confer antifungal activity.
• Summarize absorption, distribution, metabolism, and excretion, emphasizing factors that affect bioavailability.
• Identify approved therapeutic indications, common off‑label uses, and safety considerations.
• Recognize major drug–drug interactions and patient populations requiring special monitoring.

Classification

Drug Class

Itraconazole belongs to the triazole class of antifungal agents, characterized by a 1,2,4-triazole ring that is conjugated with a secondary triazole moiety. Within the broader category of azoles, itraconazole is classified as a second‑generation agent, designed to enhance activity against Aspergillus spp. and to improve pharmacokinetic properties relative to first‑generation agents such as fluconazole.

Chemical Classification

The molecular formula of itraconazole is C₂₈H₂₇Cl₁N₆O₅. It exists in a mixture of isomers; the (R,R)-enantiomer predominates in the marketed formulation. The compound is highly lipophilic (logP ≈ 6.0) and contains several functional groups—such as ketone, ester, and ether linkages—that contribute to its physicochemical behavior and metabolic stability.

Mechanism of Action

Pharmacodynamics

Itraconazole exerts its antifungal effect primarily by inhibiting the cytochrome P450–dependent lanosterol 14α‑demethylase (CYP51) enzyme. This enzyme is essential for the conversion of lanosterol to ergosterol, a critical component of fungal cell membranes. Inhibition of CYP51 leads to accumulation of toxic methylated sterols and depletion of ergosterol, resulting in compromised membrane integrity, altered membrane permeability, and ultimately fungal cell death. The drug displays fungistatic activity against Candida spp. and fungicidal activity against Aspergillus spp. and dermatophytes.

Molecular and Cellular Mechanisms

Binding of itraconazole to the heme iron within the active site of CYP51 is mediated through its triazole nitrogen atoms. The interaction is reversible but has a high affinity, yielding an inhibition constant (K_i) in the low nanomolar range for Aspergillus strains. Cellular uptake of itraconazole is facilitated by passive diffusion due to its lipophilicity; however, efflux pumps such as P-glycoprotein can attenuate intracellular concentrations in some fungal species. Additionally, itraconazole may interfere with the synthesis of other ergosterol‑dependent enzymes, further disrupting fungal physiology.

Pharmacokinetics

Absorption

Oral absorption of itraconazole is highly variable and dependent on formulation, food intake, and gastric pH. The capsule formulation exhibits superior bioavailability when taken with a high‑fat meal, whereas the solution formulation shows less dependence on food but remains susceptible to acidic conditions. In patients receiving proton pump inhibitors or H2‑receptor antagonists, the bioavailability of the capsule can be reduced by up to 50%, necessitating dose adjustments or formulation changes. Peak plasma concentrations (C_max) are typically reached within 1–2 hours following ingestion of the solution; capsules may take 4–6 hours. The bioavailability of the capsule ranges from 10–20% under fasting conditions but can rise to 50–70% with a fatty meal.

Distribution

Itraconazole is extensively distributed into tissues, with a volume of distribution (V_d) approximating 250–400 L in adults. The drug demonstrates strong plasma protein binding (>90%), primarily to albumin and α‑1‑acid glycoprotein. Tissue concentrations in the lungs, spleen, liver, and kidneys are markedly higher than plasma levels, facilitating efficacy against pulmonary aspergillosis and systemic candidiasis. The drug also penetrates the central nervous system, although CNS concentrations are lower than peripheral tissues, limiting its utility for invasive meningitis caused by susceptible fungi.

Metabolism

Hepatic metabolism is mediated predominantly by cytochrome P450 isoenzymes CYP3A4 and CYP2C19. The metabolic pathway yields several metabolites, including 17‑hydroxyitraconazole, which retains antifungal activity but at a lower potency. The metabolic clearance is variable, with a half‑life (t_1/2) of approximately 25–35 hours for the solution formulation and 30–45 hours for the capsule. Due to extensive first‑pass metabolism and enterohepatic recirculation, steady‑state concentrations are achieved after 5–7 days of continuous therapy.

Excretion

Excretion occurs primarily via the biliary route, with a minor urinary component (<5% of the dose). Renal elimination is negligible; hence, dose adjustments are generally unnecessary in patients with renal impairment. In patients with hepatic dysfunction, plasma concentrations rise, and dose reductions or extended dosing intervals may be warranted to avoid toxicity.

Half‑Life and Dosing Considerations

The prolonged half‑life permits once‑daily dosing for most indications, although the solution formulation may require twice‑daily administration in certain severe infections. Loading doses are frequently employed to attain therapeutic levels rapidly; typical regimens involve a 200 mg dose twice daily for 3–5 days, followed by a maintenance dose of 200 mg once daily. The pharmacokinetic variability underscores the importance of therapeutic drug monitoring (TDM) in patients receiving concurrent medications that alter gastric pH or hepatic metabolism.

Therapeutic Uses and Clinical Applications

Approved Indications

Itraconazole is approved for the treatment of invasive aspergillosis, subcutaneous sporotrichosis, and various dermatophyte infections such as tinea corporis and tinea capitis. It is also indicated for onychomycosis caused by dermatophytes and Candida spp. In certain jurisdictions, itraconazole is licensed for the treatment of cryptococcosis and mucormycosis, although alternative agents may be preferred in severe cases.

Off‑Label Uses

Due to its broad spectrum, itraconazole is frequently employed off‑label for invasive candidiasis, histoplasmosis, blastomycosis, and paracoccidioidomycosis. It is also used in prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation or receiving prolonged systemic corticosteroids. The efficacy in these settings is supported by clinical experience, yet robust randomized data are limited, highlighting the need for individualized risk–benefit assessment.

Adverse Effects

Common Side Effects

Gastrointestinal disturbances—including nausea, vomiting, dyspepsia, and abdominal pain—represent the most frequently reported adverse events. Dermatologic manifestations such as rash, pruritus, and photosensitivity may occur, especially in patients with high plasma concentrations. Hepatic enzyme elevations (alanine aminotransferase, aspartate aminotransferase) are observed in up to 10% of patients and may necessitate dose modification or discontinuation if levels rise >5× the upper limit of normal.

Serious or Rare Adverse Reactions

Cardiovascular complications such as QT prolongation and torsades de pointes have been documented, particularly in patients receiving concomitant QT‑shortening agents or with pre‑existing conduction abnormalities. Severe hepatotoxicity, including fulminant hepatic failure, remains uncommon but potentially fatal; it is more likely in patients with pre‑existing liver disease or when combined with other hepatotoxic medications. Ototoxicity, manifested by tinnitus or hearing loss, has been reported in isolated cases and may be dose‑related.

Black Box Warning

A boxed warning highlights the risk of hepatotoxicity, recommending monitoring of liver function tests (LFTs) before initiation and periodically thereafter. The warning also cautions against use in patients with severe hepatic impairment and underscores the necessity of dose adjustment or alternative therapy in such individuals.

Drug Interactions

Major Drug–Drug Interactions

Itraconazole is a potent inhibitor of CYP3A4, which can elevate plasma concentrations of co‑administered drugs metabolized by this pathway, including certain statins (e.g., simvastatin), benzodiazepines, and calcium channel blockers. Conversely, strong CYP3A4 inducers such as rifampin or carbamazepine can markedly reduce itraconazole levels, compromising efficacy. Additionally, itraconazole competes for P-glycoprotein transport, potentially affecting the disposition of drugs like digoxin.

Contraindications

Itraconazole is contraindicated in patients with hypersensitivity to triazole derivatives, uncontrolled hepatic failure, or concomitant use of drugs that are contraindicated with potent CYP3A4 inhibition. The drug should be avoided in pregnancy category D patients, as data suggest potential teratogenicity in animal studies, and in lactation unless the benefits outweigh potential risks to the infant.

Special Considerations

Use in Pregnancy and Lactation

Limited human data exist regarding itraconazole exposure during pregnancy. Animal studies indicate a risk of fetal malformations at doses exceeding the human therapeutic range; therefore, the drug is generally avoided unless alternative antifungals are unsuitable. During lactation, itraconazole is excreted into breast milk at low concentrations; however, the potential for drug accumulation in the infant and the lack of controlled safety data warrant cautious use.

Pediatric and Geriatric Considerations

In pediatric patients, dosing is weight‑based, typically ranging from 5 mg/kg daily for mild infections to 10 mg/kg daily in severe cases. Growth, development, and organ maturation may influence pharmacokinetics; hence, therapeutic drug monitoring is advisable. In elderly patients, diminished hepatic function and polypharmacy increase the risk of drug interactions and hepatotoxicity; lower maintenance doses and vigilant monitoring are recommended.

Renal and Hepatic Impairment

Renal impairment has minimal impact on itraconazole elimination; dose adjustment is generally unnecessary. In hepatic impairment, plasma levels rise due to reduced metabolism; a 50% dose reduction or extended dosing intervals is often implemented. Monitoring of liver function tests is mandatory, and discontinuation may be required if significant hepatotoxicity develops.

Summary and Key Points

Key Takeaways

• Itraconazole is a second‑generation triazole antifungal that inhibits lanosterol 14α‑demethylase, disrupting ergosterol synthesis.
• Its pharmacokinetics are highly variable; food, gastric pH, and hepatic metabolism critically influence bioavailability.
• Approved indications include invasive aspergillosis, sporotrichosis, and dermatophyte infections; off‑label uses encompass a broad range of systemic fungal diseases.
• Common adverse events involve gastrointestinal upset and hepatic enzyme elevations; serious effects include QT prolongation and hepatotoxicity.
• Strong CYP3A4 inhibition underlies many drug interactions; therapeutic drug monitoring is advised, especially in patients on interacting medications.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, hepatic impairment—require particular caution and dose adjustments.

Clinical practice benefits from integrating pharmacokinetic knowledge, vigilant monitoring, and individualized dosing to maximize itraconazole efficacy while minimizing toxicity. Ongoing research into pharmacogenomics and novel formulations may further refine its therapeutic profile in the future.

References

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