Itraconazole Professor David W. Denning Professor of Infectious Diseases in Global Health National Aspergillosis Centre, Manchester, UK The University of Manchester, UK

Part 1: Intended learning outcomes Structure of itraconazole Mechanism of action of itraconazole Spectrum of activity of itraconazole

Itraconazole structure A synthetic triazole Second-generation triazole Molecular weight ~706 g/mol Structurally similar to ketoconazole and posaconazole Posaconazole

Mechanism of action Preferentially binds fungal cytochrome P450-enzyme lanosterol C-14-α demethylase Inhibits the conversion of lanosterol to ergosterol – major constituent of fungal cell membrane Resulting in the accumulation of fungal 14 alpha-methyl sterols, the loss of normal fungal sterols, and fungistatic activity. Mammalian cell demethylation is much less sensitive to itraconazole inhibition.

Squalene monooxygenase Mechanism of action Acetyl-CoA Squalene 2,3-oxidosqualene Lanosterol C-14α demethylase Squalene monooxygenase Azoles Ergosterol

Spectrum of activity Yeast Dimorphic Dermatophytes Candida spp. + C. krusei Cryptococcus spp. Dimorphic B. dermatitidis, Coccidioides spp., Histoplasma spp., Paracoccidioides spp. Dermatophytes Microsporum spp, Epidermophyton spp and Trichophyton spp. Moulds: Aspergillus spp., Sporothrix spp.; minimal activity against Fusarium spp.; no activity against Scedosporium spp. Mucorales: Minimum activity. Itraconazole = fluconazole + Aspergillus coverage + better activity against endemic fungi

Spectrum of activity of triazole Fungi Fluconazole Itraconazole Voriconazole Posaconazole Candida albicans +++ Candida glabrata +/- + Candida krusei - Cryptococcus spp. ++ Aspergillus fumigatus Aspergillus terreus Blastomyces spp. Coccidioides spp. Histoplasma spp. Sporothrix spp. Fusarium spp. Scedosporium spp. Mucorales

Part 2: Intended learning outcomes To understand the pharmacokinetics of itraconazole To be aware of the different formulations of itraconazole

Improves bioavailability No effect Gastric acid effect Distribution Pharmacokinetics Parameter Capsule Oral solution Bioavailability 55% 80% Food effect Improves bioavailability No effect Gastric acid effect Distribution Poor CNS penetration Protein binding 99.8% Metabolism Liver (extensive); CYP3A4 Main metabolite Hydroxy-itraconazole (bioactive) Half life 21 hours Excretion Urine (35%); faeces (54%)

Pharmacokinetic profiles Triazole Solubility Absorption Food effect Bioavailability T1/2 (h) Excretion Fluconazole High - >90% 20-50 Renal Itraconazole * Low Erratic ++ 55% 24-42 Hepatic Voriconazole 96% 6 Posaconazole # * Itraconazole absorption is better with solution ~ 80% # Posaconazole absorption is better with tablets ~ 2–3x

Target therapeutic ranges Drug Therapeutic range (mcg/mL) Toxic level CYPs inhibited Rationale for TDM 5-flucytosine >25 >100 n/a Clearance in renal disease Fluconazole 4–20 not established 2C19, 3A4 Select patients only Itraconazole >0.5 (localized) >1.0 (systemic) Increases with levels 3A4 Variable absorption, avoidance of high levels Voriconazole 1.0–5.5 >6.0 2C9, 3A4 Nonlinear kinetics

Formulations Oral Parenteral Capsules: 100 mg Solution: 10 mg/ml; 150 ml bottle Parenteral 10 mg/ml; 25 ml ampoule

Part 3: Intended learning outcomes Clinical indications for itraconazole Dosing of itraconazole for various indications Side effect profile of itraconazole

Clinical indications Oropharyngeal/eosophageal candidiasis Vulvovaginal candidiasis Pityriasis versicolor Tinea corporis, cruris, pedis and manuum Onychomycosis Aspergillosis Histoplasmosis Coccidiodomycosis Systemic candidiasis Cryptococcosis Primary prophylaxis Secondary prophylaxis

Oropharyngeal/oesophageal candidiasis Dose Oropharyngeal/oesophageal candidiasis 20 ml daily, 1-2 divided doses, 7 days, capsules ineffective, solution better Continue 7 more days if no response If previously failed fluconazole therapy 10-20 ml , BD, 2 weeks Continue for 2 more weeks if no response

Vulvovaginal candidiasis 200 mg twice over the course of 24 hours

Pityriasis versicolor 200 mg, OD, 7 days

Tinea infection Tinea corporis and tinea cruris 100 mg, OD, 15 days or Tinea pedis and tinea manuum 100 mg, OD, 30 days or 200 mg, BD, 7 days

Onychomycosis Either 200mg, OD, 3 months Or (‘Pulse’) therapy: 200mg, BD, 7 days Fingernails: 2 courses Toenails: 3 courses 21- day interval between course

Aspergillosis Chronic forms of aspergillosis Chronic pulmonary aspergillosis Allergic bronchopulmonary aspergillosis Orally: 200mg, BD; long-term – solution preferred if on PPI

Histoplasmosis 200mg, TDS, 3 days loading doses then 200mg, OD/BD long-term Use 200mg twice daily as solution in AIDS, as absorption may be poor

Systemic infections Cryptococcal meningitis (if fluconazole is contraindicated, or treating concurrent other fungal infections) Maintenance phase: 200mg , BD Candidaemia (rarely used - where other agents are inappropriate or ineffective) 100-200mg, OD Doses should be increased in disseminated infections

Primary prophylaxis Indication: Haematological malignancy Chemotherapy HSCT Dose 5mg/kg, daily, 2 divided dose, capsules ineffective – solution superior Before chemotherapy or HSCT Continued until neutrophil count recovers

Side effects: common GIT Liver CNS Nausea Vomiting Taste disturbances Abdominal pain Diarrhoea Liver Hepatitis Hepatotoxicity CNS Peripheral neuropathy Headache Dizziness Others Dyspnoea Hypokalaemia Rash Pedal oedema Visual disturbances

Side effects: less commonly GIT Dyspepsia Flatulence Constipation CNS Dizziness Tremor Confusion, Drowsiness Tinnitus Deafness Endocrine Hypertriglyceridemia Pancreatitis Hyperglycaemia Alopecia Erectile dysfunction Adrenal dysfunction (inhaled steroids) Skin Photosensitivity Toxic epidermal necrolysis Stevens-Johnson syndrome Haematology Thrombocytopenia Leukopenia Others Blood pressure changes Renal impairment Arthralgia Menstrual disorder Myalgia Heart failure Urinary frequency Tiredness

Itraconazole Pros Cons Safe Effective Excellent tissue penetration Hepatotoxic Fungistatic Cross resistance GI intolerance Fluid retention Inhibition CYP3A4 LV dysfunction TDM is recommended for long term therapy

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