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

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

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

4. 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.

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

6. 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

7. 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

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

9. 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%)

10. 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

11. 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

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

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

14. 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

15. 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

16. Vulvovaginal candidiasis
200 mg twice over the course of 24 hours

17. Pityriasis versicolor
200 mg, OD, 7 days

18. 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

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

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. Thank You