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David W. Denning National Aspergillosis Centre, Manchester, UK
Itraconazole David W. Denning National Aspergillosis Centre, Manchester, UK
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Part 1: Intended learning outcomes
To appreciate the structure of itraconazole To understand the mechanism of action of itraconazole To be aware of the spectrum of activity of itraconazole
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Itraconazole structure
A synthetic triazole Second generation Triazole Molecular weight of ~706 g/mol Structurally similar to ketoconazole and posaconazole Posaconazole
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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.
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Squalene monooxygenase
Mechanism of Action Acetyl-CoA Squalene Squalene -2,3 oxide Lanosterol C-14α demethylase Squalene monooxygenase Azoles Ergosterol
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Spectrum of activity Yeast Dimorphic Dermatophytes
Candida spp. + C. krusei Cryptococcus spp. Dimorphic B. dermatitidis, Coccidioides spp., Histoplasma spp. Dermatophytes Microsporum spp, Epidermophyton spp and Trichophyton spp. Moulds: Aspergillus spp, Sporothrix spp; minimum activity on Fusarium spp , no activity on Scedosporium spp Mucorales: Minimum activity. Itraconazole = fluconazole + Aspergillus coverage + better activity against endemic fungi
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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
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Part 2: Intended learning outcomes
To understand the Pharmacokinetics of itraconazole To be aware of the different formulations of itraconazole
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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%)
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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
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Target therapeutics ranges
Drug Therapeutic range (mcg/mL) Toxic level CYPs inhibited Rationale for TDM 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 >6.0 2C9, 3A4 Nonlinear kinetics
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Formulations Oral Parenteral Capsules:100mg
Solution:10mg/mL; 150mL bottle Parenteral 10mg/mL; 25-mL ampoule
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Part 3: Intended learning outcomes
To be aware of the clinical indications for itraconazole To be familiar with the dosing of itraconazole for the various indications To be aware of the side effect profile of itraconazole
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Clinical indication Oropharyngeal/oroesophageal candidiasis
Vulvovaginal candidiasis Pityriasis versicolor Tinea corporis, cruris, pedis and manuum Onychomycosis Aspergillosis Histoplasmosis Coccidiodomycosis Systemic candidiasis Cryptococcosis Primary prophylaxis Secondary prophylaxis
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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 failed Fluconazole therapy 10-20 mL , BD, 2 weeks Continue for 2 more weeks if no response
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Vulvovaginal candidiasis
200mg twice over 24 hours, 1 day
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Pityriasis versicolor
200mg, OD, 7 days
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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
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Onychomycosis Either 200mg, OD, 3 months
Or (‘Pulse’) therapy: 200mg, BD, 7 days Fingernails: 2 courses Toenails: 3 courses 21- day interval between course
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Aspergillosis Chronic forms of aspergillosis
Chronic pulmonary aspergillosis Allergic bronchopulmonary aspergillosis Orally: 200mg, BD; long-term – solution preferred if on PPI
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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
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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) mg, OD Doses should be increased in disseminated infections
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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
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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
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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
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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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Thank You
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