Itraconazole

Summary

Synopsis

Itraconazole is an orally active triazole antifungal drug which has demonstrated a broad spectrum of activity and a favourable pharmacokinetic profile. It is a potent inhibitor of most human fungal pathogens including Aspergillus sp.

In non-comparative clinical trials itraconazole was shown to be extremely effective in a wide range of superficial and more serious ‘deep’ fungal infections when administered once or twice daily. Generally, greater than 80% of patients with superficial dermatophyte or yeast infections are cured by itraconazole. Similarly, good to excellent response rates (clinical cure or marked improvement) are achieved in paracoccidioidomycosis, histoplasmosis, sporotrichosis, blastomycosis, systemic candidiasis, coccidioidomycosis, chromomycosis, aspergillosis and cryptococcosis. Understandably, given the rare nature of some of these diseases, clinical experience is relatively limited and further evaluation, preferably controlled trials with amphotericin B and ketoconazole, would help clarify the ultimate role itraconazole will have in their management. Preliminary findings also indicate that itraconazole may hold promise for the prophylaxis of opportunistic fungal infections in patients at risk, for example women with chronic recurrent vaginal candidiasis, immunodeficient patients with chronic mucocutaneous candidiasis, AIDS patients and patients receiving immunosuppressant drugs. In studies to date itraconazole has been very well tolerated. Transient changes in indices of liver function occurred in I to 2% of patients; however, symptomatic liver dysfunction (as occurs infrequently with ketoconazole) has not been reported. Wider clinical experience is needed to permit clear conclusions as to whether liver dysfunction can result from itraconazole administration.

Thus, while several aspects of the drug’s profile require further investigation, itraconazole is a promising new oral treatment of fungal disease. The extent to which itraconazole will be employed in preference to ketoconazole will be clarified by wider clinical experience.

Pharmacodynamic Studies

Itraconazole was active in vitro against a wide variety of fungi with a spectrum of activity which qualitatively resembles that of ketoconazole, the first oral azole to gain widespread acceptance. This spectrum includes dermatophytes (e.g. Microsporum, Trichophyton and Epidermophyton species), yeasts (e.g. Candida spp., Pityrosporum spp. and Cryptococcus neoformans), dimorphic fungi (e.g. Histoplasma, Paracoccidioides brasiliensis, Blastomyces dermatitidis and Sporothrix schenckii), various organisms which cause chromomycosis, and other fungi including Aspergillus fumigatus. Quantitatively itraconazole was more potent than ketoconazole, although in vitro results vary considerably depending on culture medium, inoculum size, conditions of incubation, etc. Because of the variability of in vitro results these tests may not necessarily reflect in vivo efficacy.

In in vivo models of superficial mycoses itraconazole was effective orally and topically in treating dermatophytic infections. Cutaneous candidiasis in guinea-pigs and vaginal candidiasis in the pseudoestrus rat were cured by itraconazole. In guinea-pigs injected intravenously with Candida albicans, itraconazole improved the survival rate at a dosage of 0.63 mg/kg/day and prevented systemic disease at 5 mg/kg/day administered for 21 days. While all control animals infected with Aspergillus fumigatus died, > 80% of guineapigs, including immunocompromised animals, treated with itraconazole 5 mg/kg/day survived and most were culture negative and free of organ necrosis. Itraconazole 200mg daily sterilised the cardiac vegetations of rabbits infected with A. fumigatus and improved the survival rate of these animals in comparison to those treated with amphotericin B and/or 5-fluorocytosine. In in vivo models of cryptococcal meningitis itraconazole sterilised CSF cultures in the majority of animals. Higher doses of itraconazole (40 mg/kg/ day) cured guinea-pigs with a disseminated infection of Sporothrix schenckii and Histoplasma capsulatum var. duboisii. Itraconazole 200 mg/kg/day administered for 7 weeks effected parasitological cure in mice infected with a virulent inoculum of Trypanosoma cruzi.

The mechanism of action of itraconazole relates to its binding of fungal cytochrome P-450 isozymes with resultant inhibition of ergosterol synthesis and perturbation of membrane-bound enzyme function and membrane permeability. Itraconazole binds more avidly to fungal cytochrome P-450 than does ketoconazole and, unlike ketoconazole, has little effect on mammalian cytochrome P-450 enzyme systems. There is some preliminary evidence that fungal killing by host defence cells is facilitated by the antifungal activity of itraconazole, although the clinical significance of this is not yet clear.

Pharmacokinetic Studies

Following oral administration of itraconazole peak plasma concentrations are reached within 1.5 to 4 hours. Absorption varies between individuals but is improved when the drug is administered with a meal and this schedule is recommended to maximise therapeutic effect. Steady-state plasma concentrations are achieved after 14 days’ administration and the concentrations attained with 100mg daily (peak and trough concentrations of 0.6 and 0.2 mg/L, respectively) should be effective against most common fungal pathogens.

Itraconazole is widely distributed in the body, achieving concentrations in some tissues up to 10 times higher than corresponding plasma concentrations. Itraconazole can be detected in stratum corneum up to 4 weeks after discontinuing therapy, which probably reflects the drug’s affinity for sebum and for keratinocytes. Low to negligible concentrations of itraconazole are found in cerebrospinal fluid. The drug is 95% protein bound, primarily to albumin. Only 0.2% of itraconazole in plasma is present as free drug, the remainder being bound to blood cells.

Itraconazole undergoes extensive hepatic metabolism prior to being excreted in inactive form in urine and bile. Itraconazole biotransformation may be a saturable process at clinically useful dosages leading to disproportionate increases in AUC for a given dosage increment. The elimination half-life in healthy volunteers is about 20 hours after a single oral dose of 100mg and approximately 30 hours following 2 to 4 weeks’ treatment with itraconazole 100mg once daily. In patients with renal impairment, the disposition of itraconazole does not differ significantly from that of healthy subjects. Haemo- and peritoneal dialysis have a negligible effect on itraconazole clearance, hence dosage supplements are not necessary. Preliminary evidence suggests that dosage adjustment is not required in patients with liver dysfunction; however, further studies are needed to confirm these findings.

Therapeutic Use

Most clinical experience with itraconazole in superficial mycoses has been gained from non-comparative studies, particularly a few large multicentre trials and some dose-finding clinical trials. Overall, itraconazole 100mg once daily has proven to be the optimal dosage in dermatophytoses, producing ⩾ 80% clinical and mycological response (cure or marked improvement) against tinea corporis, tinea cruris, tinea pedis and tinea manuum. Itraconazole 50mg once daily elicited less consistent results, while there is some evidence that a higher dosage (200mg once daily) may permit shorter courses of treatment. In very limited experience with the treatment of tinea capitis, itraconazole 100mg once daily produced an excellent therapeutic response, although therapy was more prolonged (3 to 7 weeks). Compared with griseofulvin 500mg (ultramicronised) once daily itraconazole 100mg once daily was superior in terms of mycological clearance in patients with various tinea infections, and it also produced a significantly better clinical response in patients with tinea corporis and tinea cruris. Studies in patients with pityriasis versicolor showed that, provided the total dosage was ⩾ 1000mg, itraconazole cured more than 90% of patients and helped reduce the number of early relapses. Itraconazole 200mg daily for 5 days was found to be as effective as selenium sulphide 2.5% shampoo but tended to be better tolerated. Reduction in P. orbiculare colonisation during treatment with itraconazole 50 to 100mg daily was associated with clearing or marked improvement of lesions in a small number of patients with sebopsoriasis. In women with acute vaginal candidiasis itraconazole maintained initial mycological clearance during a follow-up period of 4 weeks in at least 80% of patients provided a minimum total dosage of 400mg had been administered. For recalcitrant vaginal candidiasis itraconazole 200mg once daily for 3 days produced the best results; symptoms such as leucorrhoea, pruritus, dysuria and dyspareunia were relieved in > 90% of cases. Preliminary data indicate that one day’s treatment with itraconazole (400mg in 2 divided doses) produced mycological cure in > 80% of women with acute infection and that a single 200mg dose on the first day of menses may provide effective prophylaxis in patients with chronic recurrent disease.

Itraconazole 100mg once daily has also proven useful in fungal diseases such as chronic mucocutaneous candidiasis and chromomycoses although, as expected, much longer durations of treatment have been necessary. Further study is needed to determine whether itraconazole can maintain a remission in these problematic conditions, particularly in chronic mucocutaneous candidiasis patients.

As expected, far fewer patients with systemic mycoses have been treated with itraconazole, and it is probably too early to clearly define how useful it will prove in these diseases. However, preliminary experience is extremely encouraging and clinical cure or significant improvement has been documented in > 80% of patients with paracoccidioidomycosis, sporotrichosis, histoplasmosis and blastomycosis. Itraconazole has also proven very useful in the treatment of systemic candidiasis, chromomycosis, coccidioidomycosis, aspergillosis and cryptococcosis (including meningeal cryptococcosis). In most cases itraconazole dosage was initiated at 200mg daily and titrated up to 400mg in 1 or 2 divided doses if the patient failed to respond. Preliminary findings suggest that itraconazole may hold promise for the prophylaxis of invasive opportunistic fungal infections in patients at risk, for example AIDS patients and those receiving immunosuppressant drugs. Indeed, in small pilot studies itraconazole 200mg twice daily was significantly superior to ketoconazole 200mg twice daily in protecting patients undergoing immunosuppressive therapy from fatal Aspergillus infections.

Adverse Effects

Itraconazole is well tolerated by most patients, the most common side effects relating to gastrointestinal disturbances. The incidence of side effects increases with duration of treatment; administration for ⩾ 1 month results in an incidence of adverse effects of 17.7%, with a resulting dropout rate of 4.7%. Itraconazole appears to be devoid of effects on the pituitary-testicular-adrenal axis at the dosages used to date. Rarely, transient increases in liver enzymes have occurred; however, no cases of symptomatic liver dysfunction have been reported. Seven instances of hypokalaemia have been described.

Dosage and Administration

The recommended itraconazole dosage for superficial fungal infections is 100mg once daily at mealtime for: 15 days in patients with tinea corporis/cruris; 30 days, tinea pedis/ manuum; 4 to 8 weeks, tinea capitis, and a minimum of 3 to 6 months, onychomycoses. In pityriasis versicolor, vaginal candidiasis and fungal keratitis the recommended dosage is 200mg once daily for 5 days, 3 days, and 3 weeks, respectively. The initial dose in systemic mycoses is 200mg daily increased to 400mg daily in 1 or 2 divided doses when oral absorption is questionable and/or response is inadequate. Treatment length in systemic disease should be individualised by clinical and mycological response. It is recommended that treatment continue beyond an apparent mycological cure, although the length of this additional treatment has not been well defined. In children the recommended dose is 3 to 5 mg/kg/day. Itraconazole is contraindicated in pregnancy.