Itraconazole

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Itraconazole

Overview

Itraconazole is a synthetic broad-spectrum triazole antifungal, derived from ketoconazole by prolongation of its hydrophobic side chains. This structural modification enhances binding to the apoprotein of the 14α-demethylase enzyme while reducing mammalian hormonal side effects compared to ketoconazole.

Katzung's Basic and Clinical Pharmacology, 16th Ed.
Fitzpatrick's Dermatology, Vol. 1&2

Mechanism of Action

Like all azoles, itraconazole acts by inhibiting fungal cytochrome P450-dependent 14α-sterol demethylase (CYP51), which suppresses the conversion of lanosterol → ergosterol - the principal sterol of fungal cell membranes. This depletes ergosterol and causes accumulation of toxic methylated sterols, leading to increased membrane permeability and fungal cell death.

The drug is considered fungistatic (at clinical concentrations).

Fitzpatrick's Dermatology, Vol. 1&2
Lippincott Illustrated Reviews: Pharmacology

Formulations

Formulation	Key Note
Capsule (100 mg; Sporanox generics)	Requires gastric acidity + food for absorption
SUBA-capsule (65 mg; Tolsura)	Super-bioavailable; absorption not affected by food
Oral solution (10 mg/mL, cyclodextrin carrier)	Best absorbed fasting (empty stomach); ~30% higher bioavailability than capsule
IV formulation (cyclodextrin carrier)	Avoid if CrCl <30 mL/min (cyclodextrin accumulates)

The cyclodextrin (oligosaccharide ring) entraps the hydrophobic, water-insoluble drug, making it soluble for the solution/IV preparations.

Goldman-Cecil Medicine, International Edition
Harriet Lane Handbook, 23rd Ed.

Pharmacokinetics

Parameter	Details
Absorption	Capsule: enhanced by food and low gastric pH; oral solution: enhanced by fasting
Bioavailability	Variable and erratic with capsules; improved with cyclodextrin solution
Protein binding	Highly protein-bound
Distribution	Highly lipophilic; concentrates in tissues, pus, bronchial secretions, bone, adipose, and nails. Poor CNS/CSF penetration. Low ocular levels
Metabolism	Extensive hepatic metabolism via CYP3A4. Active metabolite: hydroxyitraconazole (present in plasma at ~2x the parent; similar antifungal activity)
Half-life	~21 hours at single dose; rises to 30-40 hours at steady state
Time to steady state	4-7 days (13-15 days per some sources); loading doses are recommended
Excretion	Feces as metabolites; no useful renal excretion
Nail penetration	High affinity to nail; forms drug reservoir lasting 6-9 months after stopping
Renal failure	No dose adjustment needed for oral forms; IV form should be avoided if CrCl <30 mL/min
Hepatic failure	Half-life prolonged in cirrhosis; dose adjustment needed in progressive liver disease

Fitzpatrick's Dermatology; Goldman-Cecil Medicine; Goodman & Gilman's; Katzung's

Spectrum of Activity

Itraconazole is the azole of choice for the dimorphic fungi:

Histoplasma capsulatum (histoplasmosis)
Blastomyces dermatitidis (blastomycosis)
Sporothrix schenckii (sporotrichosis)
Paracoccidioides brasiliensis (paracoccidioidomycosis)

Also active against:

Dermatophytes (tinea corporis, pedis, cruris, capitis, manuum, PV)
Candida spp. (less preferred now due to better agents)
Aspergillus spp. (active but voriconazole is now preferred for aspergillosis)
Cryptococcus neoformans

Resistant or poorly susceptible:

Candida krusei, Candida glabrata - reduced susceptibility
Candida auris - largely resistant
Mucorales (mucormycosis)
Lomentospora (Scedosporium) prolificans
Katzung's; Lippincott Illustrated Reviews; Medical Microbiology 9e; Goodman & Gilman's

Clinical Indications and Dosing

Systemic/Endemic Mycoses

Infection	Regimen
Histoplasmosis (mild-moderate)	Itraconazole 200 mg PO 3x/day x3 days, then 200 mg BID x 12 months
Histoplasmosis (moderate-severe)	Lipid amphotericin B, then step-down to itraconazole after improvement
Blastomycosis	Drug of choice
Sporotrichosis	Drug of choice
Paracoccidioidomycosis	Drug of choice
Coccidioidomycosis	Alternative agent

Dermatophyte & Superficial Infections (Fitzpatrick's)

Infection	Regimen
Tinea infections / PV	100 mg BID x 5 days
Onychomycosis (continuous)	200 mg/day x 6 weeks
Onychomycosis (pulse)	400 mg/day x 1 week/month, repeated monthly

Pediatric Dosing (Harriet Lane)

General: 3-5 mg/kg/day once daily or BID
Aspergillus prophylaxis in chronic granulomatous disease: up to 5-10 mg/kg/day
HIV-related infections: Histoplasma: 5-10 mg/kg/day; Coccidioides: 2-5 mg/kg/dose Q12h; Candida: 5 mg/kg/day

Adverse Effects

Effect	Details
GI disturbance	Most common - nausea, vomiting, diarrhea, abdominal pain
Unpleasant taste	Characteristic with cyclodextrin oral solution; major cause of non-compliance
Negative inotropic effect	Contraindicated in ventricular dysfunction / heart failure
Edema + hypertension + hypokalemia	Classic triad in elderly patients on itraconazole
Hepatotoxicity	Hepatitis, jaundice - especially with other hepatotoxic drugs; monitor LFTs
Rash	Especially in immunocompromised patients; rarely Stevens-Johnson syndrome
Peripheral neuropathy	Infrequent
Adrenal suppression	Rare
Hypokalemia	Can occur
Teratogenicity	Category C - avoid in pregnancy, especially first trimester

Lippincott Illustrated Reviews; Fitzpatrick's Dermatology; Fishman's Pulmonary; Goldman-Cecil

Drug Interactions

Itraconazole is both a CYP3A4 substrate AND a potent CYP3A4 inhibitor. It is also a P-glycoprotein inhibitor. This creates a very large and clinically important drug interaction profile.

Itraconazole = ketoconazole > posaconazole > voriconazole > fluconazole (in terms of CYP3A4 inhibition potency - Katzung's)

Drugs that REDUCE itraconazole levels (enzyme inducers - avoid):

Rifampin, rifabutin, rifapentine
Carbamazepine
Phenytoin
Barbiturates
St. John's Wort

Drugs whose levels are INCREASED by itraconazole (CYP3A4 inhibition):

Key clinically significant examples:

Drug Class	Examples
Anticoagulants	Warfarin (enhanced anticoagulation)
Benzodiazepines	Alprazolam, midazolam, triazolam
Statins	Lovastatin, simvastatin (risk of rhabdomyolysis) - avoid co-administration
Calcium channel blockers	Felodipine, others (risk of edema, hypotension)
Immunosuppressants	Cyclosporine, tacrolimus, sirolimus, everolimus
Cardiac	Digoxin, quinidine, dofetilide, ranolazine
Ergot alkaloids	Risk of ergotism
Antineoplastics	Docetaxel, vinca alkaloids, irinotecan, busulfan, and many kinase inhibitors
Antivirals (HIV)	Most PIs (ritonavir, saquinavir, darunavir, etc.)
PDE-5 inhibitors	Sildenafil, vardenafil (risk of hypotension)
Others	Pimozide, cisapride (risk of QT prolongation)

Goodman & Gilman's; Katzung's Basic & Clinical Pharmacology; Fishman's Pulmonary

Therapeutic Drug Monitoring

When used for systemic infections (e.g., histoplasmosis), serum trough levels should be measured after 2-3 weeks of therapy:

Target trough by HPLC: 1-10 μg/mL
Target by bioassay: 3-10 μg/mL (bioassay yields ~2x higher values due to hydroxyitraconazole metabolite)
Maximum safe level: should not exceed 17 μg/mL by bioassay
Fishman's Pulmonary Diseases and Disorders; Fitzpatrick's Dermatology

Key Clinical Pearls

Capsule vs. solution - opposite food effect: Capsules need food (acid environment); solution is best taken fasting. SUBA-capsule (Tolsura) works regardless of food.
Poor CSF penetration: Not suitable for fungal meningitis (unlike fluconazole).
Nail reservoir: Drug persists in nails for 6-9 months after stopping - supports pulse dosing regimens.
Heart failure warning: Has a documented negative inotropic effect; avoid in patients with pre-existing ventricular dysfunction.
Acid-dependent absorption: Antacids, PPIs, H2 blockers all reduce capsule absorption. Consider switching to oral solution or SUBA-capsule in such patients.
Loading doses recommended: Due to long time to steady-state (4-7 days), loading doses are used for serious infections.
Dimorphic fungi - drug of choice: Preferred over fluconazole for Histoplasma, Blastomyces, and Sporothrix; voriconazole is now preferred over itraconazole for Aspergillus.

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