Itraconazole

Pharmacological Actions
Itraconazole belongs to the triazole class of antifungals and exerts its primary pharmacological action by inhibiting lanosterol 14α-demethylase, a cytochrome P450 enzyme (CYP51) essential for ergosterol synthesis in fungal cells. Ergosterol is a critical component of fungal cell membranes, and its depletion leads to increased membrane permeability, accumulation of toxic sterols, and disruption of membrane integrity, ultimately inhibiting fungal growth. This mechanism is effective against a range of fungal infections, including aspergillosis, blastomycosis, histoplasmosis, and onychomycosis. Additionally, itraconazole has an active metabolite, hydroxyitraconazole, which contributes to its antifungal activity, enhancing its efficacy in systemic infections.
The time course of these actions is influenced by the drug’s pharmacokinetics, with antifungal effects typically observed within days to weeks, depending on the infection site and severity. For example, superficial infections like oral candidiasis may show improvement within 1-2 weeks, while deeper infections like onychomycosis may require several months for complete resolution due to the time needed for nail regrowth.
Half-Life
The half-life of itraconazole varies depending on the dosing regimen and patient factors. After a single dose, the terminal half-life ranges from 16 to 28 hours, reflecting initial distribution and elimination phases. With repeated dosing, due to non-linear pharmacokinetics and accumulation, the half-life extends to 34 to 42 hours, as steady-state concentrations are typically reached within about 15 days. This prolonged half-life is particularly relevant for chronic therapy, ensuring sustained antifungal activity.
In special populations, the half-life can be affected by renal and hepatic function. For instance, in patients with mild to severe renal impairment (CrCl 50-79 mL/min, 20-49 mL/min, and <20 mL/min), mean terminal half-lives are 42-49 hours, similar to healthy subjects at 48 hours. In cirrhotic patients, after a single 100 mg dose, the elimination half-life increases to 37 ± 17 hours compared to 16 ± 5 hours in healthy subjects, indicating slower clearance in liver dysfunction.
Bioavailabilities
Bioavailability, the fraction of the administered dose that reaches systemic circulation, varies by formulation. For oral capsules, the observed absolute bioavailability is approximately 55%, with maximal absorption achieved when taken immediately after a full meal, as gastric acidity enhances dissolution. Absorption is reduced in conditions with decreased gastric acidity, such as with concurrent use of H2-receptor antagonists or proton pump inhibitors, and can be improved under fasted conditions with an acidic beverage like non-diet cola after ranitidine pretreatment.
The oral solution, formulated with hydroxypropyl-β-cyclodextrin to improve solubility, exhibits higher bioavailability. Studies indicate that the area under the curve (AUC) for the oral solution is 30-33% higher for itraconazole and 35-37% higher for hydroxyitraconazole compared to capsules, suggesting an estimated absolute bioavailability of approximately 71.5% for the solution, based on the capsule’s 55% baseline. This enhancement is attributed to better absorption, particularly in the small intestine, reducing variability seen with capsules due to intestinal epithelial damage or varying gastric environments. Notably, capsules and oral solution are not bioequivalent, and switching between formulations requires medical guidance.
Intravenous administration, while not commonly discussed in the context of oral routes, has 100% bioavailability by definition, but is less frequently used due to availability and cost considerations.
Dosages
Dosage regimens for itraconazole are tailored to the infection type, severity, and patient factors, with specific guidelines as follows:

Onychomycosis (Toenails with or without Fingernail Involvement): 200 mg orally once daily for 12 consecutive weeks, taken with a full meal.
Onychomycosis (Fingernails Only): Two treatment pulses, each consisting of 200 mg twice daily (400 mg/day) for 1 week, separated by a 3-week drug-free period.
Blastomycosis and Histoplasmosis: 200 mg once daily (2 capsules), increased in 100-mg increments to a maximum of 400 mg daily if no improvement, with doses above 200 mg/day divided into two doses, taken with food.
Aspergillosis: 200 to 400 mg daily, with a loading dose of 200 mg three times daily (600 mg/day) for the first 3 days in life-threatening situations, continued for a minimum of 3 months.
Candidiasis (Oropharyngeal): 20 mL oral solution (200 mg) once daily for 1-2 weeks, swish and swallow, or 10 mL twice daily for 2-4 weeks.
Candidiasis (Esophageal): 20 mL oral solution twice daily for 14-21 days.
Off-label Uses: For cutaneous or lymphocutaneous sporotrichosis, 200 mg daily, potentially increased to 200 mg twice daily, continued until 2-4 weeks after lesion resolution, preferring oral solution.

For renal impairment (CrCl <10 mL/min), reduce the dose by 50%; in hemodialysis or peritoneal dialysis, dose at 100 mg every 12-24 hours without supplementation. Hepatic dosing is undefined, with caution advised due to potential hepatotoxicity.
The minimum effective dose is generally 200 mg daily for most indications, reflecting the starting dose for systemic infections. The maximum dose without high risks is typically 400 mg/day, with 600 mg/day used as a loading dose in severe cases under close monitoring. Higher doses, particularly prolonged, increase the risk of adverse effects, as discussed below.
Safety, LD50, and Toxicity Thresholds
The safe dosage range is up to 400 mg/day for most patients, with higher doses (up to 600 mg/day) used short-term in life-threatening infections under medical supervision. The minimum effective dose, as noted, is 200 mg daily, ensuring therapeutic levels for most fungal infections.
The LD50, or lethal dose for 50% of test subjects, in rats is greater than 320 mg/kg orally and 100 mg/kg intraperitoneally, providing animal toxicity data. However, human LD50 is not ethically determined, and toxicity in humans is monitored through clinical parameters.
Toxicity becomes a concern at trough levels above 3 mcg/mL, with risks of hepatotoxicity and cardiotoxicity. Hepatotoxicity can manifest as elevated liver enzymes, potentially reversible upon discontinuation, with recovery typically within 6-12 weeks, though rare cases of severe liver failure have been reported. Cardiotoxicity, including congestive heart failure, is noted, particularly at doses above 400 mg/day, with a black-box warning for new or worsening heart failure. Symptoms include shortness of breath, swelling, and rapid heartbeat, necessitating immediate discontinuation and medical evaluation.
The point at which itraconazole becomes too dangerous is when these serious adverse effects appear, often linked to prolonged high doses or pre-existing liver/heart conditions. Regular monitoring of liver function tests (LFTs) at baseline and periodically, especially beyond one month of therapy, is recommended, along with drug concentration monitoring to ensure trough levels remain below 3 mcg/mL. There is no specific antidote for itraconazole overdose, and management is supportive, focusing on symptom control and discontinuation.