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   Chemistry
   Microbiology
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   CONCENTRATION-EF...
   Therapeutic use
   Toxicology
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GUEST ARTICLE
Year : 1991  |  Volume : 57  |  Issue : 1  |  Page : 4-16

Focus on itraconazole




Correspondence Address:
Greet Cauwenbergh


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How to cite this article:
Cauwenbergh G, Stoffels P. Focus on itraconazole. Indian J Dermatol Venereol Leprol 1991;57:4-16

How to cite this URL:
Cauwenbergh G, Stoffels P. Focus on itraconazole. Indian J Dermatol Venereol Leprol [serial online] 1991 [cited 2018 Nov 18];57:4-16. Available from: http://www.ijdvl.com/text.asp?1991/57/1/4/3608


Itraconazole is a new, orally active, broad-spectrum antifungal agent which is registered or in different phases of the registration pro­cess in most countries of the world. The trade­mark name is Sporanox®, except in the Neth­erlands (Trisporal®) and Germany (Sempera®). Apart from the fact that it has a broader spectrum of activity than any other azole an­tifungal, itraconazole shows interesting phar­macokinetic features in terms of its excellent tissue distribution. These properties have led to shorter therapies in vaginal candidosis and dermatomycosis, and to a more effective or better tolerated treatment of several deep mycoses, including aspergillosis, candidosis, histoplasmosis and cryptococcosis.


  Chemistry Top


All of the antifungal azoles possess a five ­member azole ring. The major structural pecu­liarity of the triazole antifungal itraconazole is that it has three nitrogen atoms in the azole ring, in contrast to the imidazoles (e.g. ketoconazole), which contain only two. [Figure - 1]

Itraconazole, on (±)-cis-4-[4-[4-[4-[[2-(2,4­dichlorophenyl)-2-(1 H-1, 2, 4-triazol-1-ylmethyi)­1,3-dioxolan-4-yl]methoxy]phenyl]-1­piperazinyl]phenyl]-2,4-dihydro-2-(1­methylpropyl)-3H-1, 2, 4-triazol-3-one, is a weak base (pKa 3-7) and is practically un-ionized at physiologic pH. The almost white to slightly yellowish powder is water insoluble: log P>5 (n-octanol-aqueous buffer, pH 6).


  Microbiology Top


Spectrum of activity

The activity of itraconazole has been evaluated on 6113 strains belonging to 252 species. Most of the human pathogens and a large number of saprophytes, including der­matophytes, yeasts, Aspergillus spp., Penicil­lium spp., dimorphic fungi and various phaeohyphomycosis, have been shown to be highly sensitive to itraconazole. Complete inhi­bition for most strains was obtained at concen­trations ranging from 0.01 .tg/ml to 1µg/ml. The majority of Fusarium species and the Zygomycetes present poor sensitivity [Table - 1].

Not only has itraconazole been found to be fungistatic at low concentrations, but it has also been observed to be fungicidal for tested organisms, such as Candida albicans, C. tropicalis, Aspergillus fumigatus and Crypto­coccus neoformans[1].

Animal models

Itraconazole was dissolved in polyethylene glycol for oral and topical treatment and in hydroxypropyll-β-cyclodextrin for oral, topical and parenteral treatment.

Topical and oral treatment were success­ful in microsporosis, trichophytosis, skin and vaginal candidosis, pityrosporosis and eye mycosis caused by Candida, Fusarium and Aspergillus. A one-day topical or oral treatment was able to cure vaginal candidosis.

The same results could not be obtained with any of the reference compounds (griseofulvin, terbinafine, ketoconazole or fluconazole) on a mg-per-kg-body-weight ba­sis, or on a % concentration basis. Antifungal levels were determined by bioassay : biologi­cally active antifungal levels were present in plasma and vaginal fluid of rats, after one oral dose of 10 mg.kg -1 for at least 72 and 96 hours respectively. These findings corresponded closely with those on prophylaxis of vaginal candidosis. Also, itraconazole was success­fully used in normal animals and animals immunodepressed with various agents in dis­seminated and systemic diseases: trichophytosis, sporotrichosis, histoplasmosis, candidosis, aspergillosis and cryptococcosis. Oral and parenteral treatment with itraconazole was compared in various models with oral and parenteral fluconazole and with parenteral amphotericin B. The outcome with itraconazole was better than with the other antifungals. Meningeal cryptococcosis responded very well to itraconazole. Combination therapy with itraconazole and fluconazole was not superior to treatment with itraconazole alone. No side effects were observed in relation to itraconazole treatment. [2]

Mechanisation of action

The triazole have a similar mechanism of action to that of the imidazoles. The free azole nitrogen competes for oxygen at the catalytic heme iron atom of cytochrome P-450 enzymes. Inhibition of cytochrome P-450 enzymes pre­vents the synthesis of ergosterol in fungal cell membranes by limiting C14 demethylation of lanosterol, which is critical in the synthesis of ergosterol. Lack of ergosterol may alter mem­brane fluidity and steric relationships of other membrane-associated enzymes, as well as causing an accumulation of phospholipids and unsaturated fatty acids within fungal cells and disrupting chitin synthesis. Unlike ketoconazole, itraconazole binds only weakly to mammalian cytochrome P-450 and it has a much higher affinity than ketoconazole for fungal P-450 enzymes.

The antifungal effect may also be due to direct membrane damage after an attack on membrane phospholipids. Another postulated mechanism is that the azoles inhibit cytochrome C oxidative and peroxidative enzymes. The fi­nal result would be an increase in intracellular peroxide generation, which may contribute to degeneration of subcellular structures. [3]

Resistance mechanisms:

Resistance rarely develops but it has been observed for C. albicans in some patients with chronic mucocutaneous candidosis. If resis­tance is present, cross-resistance to azoles is also usually observed[4]


  Pharmacokinetics Top


Antifungal plasma levels of itraconazole can be measured by bioassay or by HPLC. The two methods have been compared and the higher results obtained with bioassay correlate with the HPLC results if the in vitro activity of hydroxy-itraconazole, a major metabolite, is taken into account. The HPLC method has a high specificity and sensitivity (2 ng/ml plasma), whereas the bioassay method measures total antifungal activity with a high sensitivity (<1 ng/ml.). [1],[6]

The absolute bioavailability of itraconazole capsules is 55% (± 15%) of that obtained with IN. administration. So that optimal oral absorp­tion is ensured, itraconazole should be admin­istered shortly after a meal (mean Cmax after 100 mg intake : 132 ± 67 ng/ml) since the mean C max after a 100 mg intake of the capsules under fasting is only 38 ± 20 ng/ml.

The bioavailability of itraconazole may be slightly reduced on co-administration of H 2­antagonists. However, it is unlikely that this effect would necessitate important changes in the usual dosage of itraconazole.

itraconazole exhibits dose-dependent ki­netics after oral administration, leading to a more than dose-proportional increase in the plasma levels, especially after multiple dosing.

The mean volume of distribution for itraconazole is 10.7 I/kg and the total clearance is 5.1 ml/kg (renal excretion is negligible).

Itraconazole is highly lipophilic and is ex­tensively distributed to the tissues of animals and humans (protein binding : 99.8%). Body fluids such as CSF, eye fluid and saliva con­tain low to non-detectable amounts of itraconazole, whereas in many organs and tis­sues (skin, lung, kidney, liver, fat, spleen, muscle and bone), tissue concentrations ex­ceed the corresponding plasma levels by a factor of 1.5 to 20.

Clinical trials measuring itraconazole in vaginal tissue, skin and nails have shown that adequate tissue levels (0.1 l.g/ml) are main­tained up to three days, two weeks and six months after therapy is stopped for vaginal candidosis, dermatomycosis and onychomycosis respectively. [5]


  Metabolism Top


The routes of excretion and metabolism of itraconazole have been studied in healthy male volunteers after a single oral dose of 3H­itraconazole. One week after dosing, urinary excretion of radioactivity amounted to 35% of the dose and faecal excretion represented 54% of the dose. Unchanged itraconazole could not be detected in urine and amounts of 3 to 18% of the dose were found in the faeces. These facts point to an almost complete absorption of itraconazole after oral administration and to an extensive metabolism of the fraction absorbed. Main metabolic pathways were oxidative scis­sion of the dioxolane ring, oxidative degrada­tion of the piperazine ring and aliphatic oxida­tion and N-dealkylation at the 1-methylpropyl substituent. As a result of the various meta­bolic pathways, a very large number of me­tabolites was formed, each representing less than 1-5% of the dose.



One metabolic pathway deserves special attention, since the plasma levels of this par­ticular metabolite exceed those of the parent drug. The metabolite was identified by mass spectrometry and HPLC as hydroxy itraconazole formed by (S2 -1) oxidation of the 1 -methyl propyl substituent. Hydroxy itraconazole could not be detected in urine. As the structure of hydroxy-itraconazole closely resembles that of the parent drug, the antifun­gal activity of the metabolite was investigated in some animal models. In comparison with itraconazole, the hydroxylated metabolite was less active in rats in the treatment of vaginal candidosis and 2-4 times less potent in guinea pigs in the treatment of Microsporum canis infection and of systemic candidosis. These differences in the in vivo antifungal activity between itraconazole and its, hydroxylated metabolite are most likely related to pharmaco­kinetic differences, e.g. in absorption and first-pass metabolism. The in vitro antifungal activ­ity of the two substances was similar [5]


  Pharmacology Top
[7]

The potential effects of itraconazole on en­docrine system have been extensively studied. In mammalian in vitro preparations, itraconazole did not inhibit the aromatization of androstenedione to oestrogens at concentra­tions up to 10 -5 M. In healthy male and female volunteers receiving single or multiple doses (up to 30 days) of itraconazole, no effect was observed on serum levels of basal plasma cortisol, testosterone, and aldosterone, nor on the cortisol response to cosyntropin (ACTH) and plasma prolactin nor on the response of plasma prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to an intravenous lu­teinizing hormone-releasing hormone (LHRH) challenge.

Furthermore, plasma progesterone and oestradiol levels, as well as saliva progester­one concentrations, measured daily in female volunteers, reflected a totally normal hormonal profile throughout the menstrual cycle during a five-week administration of itraconazole at 200 mg daily. In healthy female volunteers with normal, regular menstrual cycles, a single 300­mg dose of itraconazole taken during the fol­licular phase did not modify the circadian varia­tion in plasma 17(3-oestradiol levels. The same dose taken during the luteal phase had no effects on 17(3-oestradiol and progesterone levels.

In patients with systemic mycoses receiv­ing up to 200 mg itraconazole b.i.d. for several months, no change in the response of plasma cortisol to ACTH stimulation was observed. Also, patients with superficial mycoses who received 50 or 100 mg itraconazole for up to 2 months showed no change in levels of testos­terone, sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol.

These results suggest that the changes in human sterol biosynthesis associated with ketoconazole are unlikely to occur with itraconazole at the recommended dosages.

Effect on cholesterol

In evaluations of the effects of itraconazole on cholesterol biosynthesis in human lympho­cytes, a 50% inhibition was obtained only at a concentration more than 100 times that needed to produce a similar inhibition of ergosterol synthesis in Candida albicans. In addition, changes in plasma cholesterol levels were not observed in patients on long-term itraconazole therapy.

Cardiovascular effects.

When given at a dose 200 mg for five con­secutive weeks, itraconazole had no adverse effects on any of the cardiovascular parameters evaluated (heart rate, blood pressure, ECG in­tervals and systolic time intervals). This finding was confirmed in cancer patients who received 50 mg itraconazole daily for almost one year.

Immunological effects

Itraconazole 200 mg given daily for five weeks to six healthy volunteers did not seem to have a negative influence on the following immune functions: OKT monoclonal antibodies OKT 3 , OKT 2 , OKT 4 , OKT 8 and the ratio OKT 4/ OKT 8 , neutrophil phagocytosis and chemotaxis, and E-rosette forming cells.

Other effects

No ocular effects were shown by ophthalmoscopy, slit-lamp microscopy or visual acuity testing in cancer patients receiving 50 mg itraconazole for almost one year. No signs of ocular toxicity were observed in patients treated for keratomycosis: in most patients, visual acuity improved during therapy with 200 mg itraconazole.

No photosensitivity was observed in normal adults after a 14-day treatment with itraconazole 100 mg once daily.


  CONCENTRATION-EFFECT RELATIONSHIP Top


The high tissue/plasma concentration ratio is advantageous for all indications. Plasma concentrations varied from 0.1 µg/ml to 1.0 µg/ml in pharmacokinetic trials. The actu­ally measured tissue levels as well as the cal­culated corresponding tissue levels varied from 0.15 µg/9 to 20 µg/g. Complete inhibition of most yeast and fungal strains was obtained at concentrations from 0.01 g/ml to 1.0 .tg/ml. [5]

PHARMACY

Itraconazole (Sporanox®) is available as pink and blue capsules, containing 100 mg of itraconazole in a pellet formulation supplied in blister packs with either 4, 6 or 15 capsules. Sporanox® has a limited stability : see expiry date on package.


  Therapeutic use Top


The indications of itraconazole, as well as the corresponding dose and treatment duration for the short-term treatment and long-term treatment of these disorders are summarized in the table below. The number of approved indications varies among countries according to the registration status.

For maximal absorption, it is essential to administer itraconazole immediately after a full meal. The capsules must be swallowed whole. Itraconazole is contra-indicated in patients who have shown hypersensitivity to the drug or its excipients.

Short term treatment schedules from the international product information document.





Clinical experience

Itraconazole is an effective agent in the treatment of superficial and systemic fungal in­fections. Clinical documentation exists on more than 13,000 patients and post-marketing fig­ures mention more than 1.5 million patient treatments up to December 1990. [8]

The feasibility of one-day therapy for vulvovaginal candidosis was assessed in dif­ferent clinical trials. A total dose of 400 mg (200 mg b.i.d.) of itraconazole given in a single day cured 80% of patients one months after the end of therapy. Subsequent pharmacoki­netic analysis indicated that therapeutic con­centrations of itraconazole persist in the vagi­nal wall for at least three days after discontinuation of therapy. A comparative trial versus topical clotrimazole showed that the one ­day itraconazole therapy is significantly supe­rior to clotrimazole treatment, with regard to mycological cure one month after the end of treatment. [9]

During short prophylactic treatment with itraconazole on day 5 and 6 of each menstrual cycle during six months, 11 out of 17 patients with chronic, recurrent vulvovaginal candidosis remained symptom-free. [10]

The treatment of skin dermatophytosis was successful in 80% of the patients as evaluated at the end of a 15-(tinea corporis, tinea cruris) or 30-day (tinea corporis, tinea cruris) or 30­day (tinea pedis, tinea manus) therapy. Analy­sis of treatment data two weeks after the end of therapy revealed cure rates that were 10­15% higher. This additional effect is explained by the prolonged concentration of itraconazole in the skin.

Comparisons of itraconazole 100 mg o.d. and griseofulvin 500 mg o.d. in dermatophytosis have shown that clinical and mycological cure rates are significantly higher for itraconazole two weeks after the end of a 15- or 30-day treatment regimen. [11],[12]

A number of trials have shown that itraconazole is efficacious in the treatment of pityriasis versicolor. A comparison with sele­nium sulphide has demonstrated that topical therapy may be associated with adverse effects in addition to practical problems arising from treatment of large body areas. Double-blind comparisons with clotrimazole and ciclopiroxolamine have also shown that in short treatment schedules itraconazole is more po­tent than or at least equivalent in potency to these topical agents. [13]

Initial results in the treatment of oropha­ryngeal candidosis in non-AIDS patients have shown that a 100-mg daily administration is equivalent to 200 mg daily during 15 days. [14] A trial comparing itraconazole 200 mg o.d. with ketoconazole 200 mg b.i.d. in oral and oesophageal candidosis in AIDS patients has shown that the two treatments are equally ef­ficacious (93% clinical response at week 4 of treatment). The relapse rate reached more than 80% in both groups within three months of treatment. This is an expected finding in AIDS patients. [15]

One of the major advantages of itraconazole is its in vitro and in vivo activity against Aspergillus spp. Several reports and individual experiences confirm these findings clinically. Response to itraconazole monotherapy was obtained in 24 of 34 patients (70.6%) with different forms of aspergillosis. Invasive pulmonary aspergillosis was cured in 15 of 18 patients (83.3%). Of 15 U.S. patients with aspergillosis, including four with neutropenia and two renal transplant recipients, responses were observed in 12 (80.0%). The same cure rate was obtained in the 10 immunocompromised patients in this sample. In pulmonary aspergilloma, the evaluation of any therapeutic approach is a major problem. Itraconazole therapy appeared to be beneficial in this indication since signs and symptoms improved during prolonged treatment. 19 A re­view of t37 cases of aspergillosis in an open international case collection is consistent with the detailed observations of the previously mentioned trials. [16],[17],[18],[19],[20]

In a large-scale comparative trial in fungal keratitis, itraconazole was significantly superior to ketoconazole and better than amphotericin B in the treatment of Aspergillus keratitis [21] Oral itraconazole has provided a breakthrough in the therapy of aspergillosis since, except for su­perficial aspergillosis, I.V. amphotericin B, with its well-known toxicity, was previously the only available antifungal agent.

A higher than 70% response rate has been obtained in different manifestations of systemic candidosis at a daily oral dose between 100 and 400 mg. Sufficiently high doses started as early as possible give the best chance of treating the disseminated, life-threatening in­fections, although a firm diagnosis remains a problem. Eight out of nine patients with chronic mucocutaneous candidosis were cured during long-term itraconazole therapy [22]

In a randomised clinical trial, the efficacy of itraconazole (200 mg b.i.d.) has been com­pared with that of amphotericin B (0.6 mg/kg daily or 0.3 mg/kg daily in combination with flucytosine) in neutropenic patients with proven or highly suspected systemic fungal infections. The overall clinical response was 10/16 (63%) for patients with itraconazole and 9/16 (56%) for patients treated with amphotericin B (p>0.90). Itraconazole seemed to be more ef­fective against Aspergillus infections, whereas amphotericin B seemed to be more effective against candidal infections, although the differ­ences were not statistically significant. [23]

The incidence of cryptococcosis, a third major opportunistic fungal infection, has in­creased dramatically during recent years, with 5 to 10% of all AIDS patients contracting this type of infection. Analysis of initial results of a case collection in this indication at a median daily dosage of 200 mg has shown a 61% response rate. [24] Larger trials at a higher daily dose of 400 mg have demonstrated the effi­cacy of itraconazole in these infections, a re­sponse rate of 90% having been obtained. [25],[26]sub6 As itraconazole does not penetrate the cere­brospinal fluid, the meningitis results are note­worthy and suggest that meningeal and paren­chymal penetration is critical. Clinical results suggest that long-term treatment with oral itraconazole is efficacious in preventing relapse of cryptococcal meningitis in AIDS patients. [27]

Itraconazole also appears to be efficacious in patients with coccidioidomycosis and the markedly low toxicity of itraconazole compared to that of amphotericin B again offers a major advantage. [28] Impressive activity has also been observed in a group of patients with refractory coccidioidal meningitis. [29] In these chronic and very-difficult-to-treat indications, it is not yet clear whether oral itraconazole is equivalent to or better than oral ketoconazole.

At a daily dosage of 200 to 400 mg, itraconazole may become the first choice in the treatment of histoplasmosis in AIDS and non­ AIDS patients. Clinical cure rates in different trials have ranged from 85 to 97%, with a symptomatic response within the first two weeks of treatment [30],[31] In the majority of patients, H. capsulatum was the causative agent, but the clinical results were similar in a small number of non-AIDS patients with histoplasmosis in­duced by H. duboisii. Only 2 of 78 patients with blastomycosis treated with itraconazole did not respond to therapy. North American blastomycosis caused by Blastomyces dermatitis may become a major U.S. indication for itraconazole. [32]

To complete this review on systemic fun­gal infections, it should be emphasized that the clinical spectrum of itraconazole also includes sporotrichosis [33], paracoccidioidomycosis [34] chromomycosis [35].[36] and phaeohyphomycosis. 37

Daily doses of 100 to 200 mg resulted in clinical and mycological cure in the majority of patients treated.

Other areas of interest are currently being studied: a small number of patients with tinea capitis have been treated successfully [38] and good results have been obtained in cutaneous lesihamaniasis. [39]

Although therapeutic efficacy might imply usefulness for prevention, trials to prove pro­phylaxis are still required. Trials in neutropaenic patients in the prophylaxis of opportunistic in­fection underline the extent of the anti-As­ pergillus activity of itraconazole. In this prob­lematic clinical population, a relationship be­tween antifungal plasma levels and efficacy against Aspergillus and Candida inflections has been suggested.[40],[41]

Basing themselves on the high itraconazole levels in nails, investigators have undertaken trials of a three-month oral treatment in onychomycosis with subsequent pulse doing. Initial results suggest that this short oral treat­ment will become a breakthrough in the man­agement of onychomycosis. [42]


  Toxicology Top


Ketoconazole represents a breakthrough in antifungal therapy although hepatic side-effects as well as interactions with mammalian steroi­dogenesis occasionally occur during prolonged treatment. The prediction of these adverse experiences is difficult but the potential for interaction with mammalian cytochrome P-450 enzymes can be evaluated in vitro.

The available data indicate that itraconazole is not a predictable hepatotoxic drug in man. Endocrine studies in man have shown that it is highly unlikely, that itraconazole would interact with steroid hormones at the normal therapeutic doses.

In rats, elevation of serum cholesterol has been observed especially after chronic expo­sure to itraconazole. This species-specific phe­nomenon has led to secondary events at toxic dose levels, especially in the long-term toxicity studies. In humans, including persons with existing hypercholesterolemia, serum choles­terol is not adversely affected by itraconazole.

In pregnant rats, itraconazole has been shown to be teratogenic at high, toxic doses. On the other hand, itraconazole is not terato­genic in the rabbit. Trials with itraconazole in adrenalectomized rats and in rats given exog­enous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are im­portant mediators for teratogenicity. Since . itraconazole does not affect adrenal function in man at therapeutic doses, the teratogenic risk in humans is estimated to be low. [43]


  Adverse experiences Top


During short-term itraconazole therapy, adverse experiences occurred in 7.0% of pa­tients with superficial mycoses. The most fre­quently reported adverse experiences were nausea (1.7%), headache (1.0%) and abdomi­nal/epigastric pain (0.8%).

During long-term therapy in patients with systemic mycoses, most of whom had a major underlying pathology and multiple concomitant treatments, the incidence of adverse experi­ences was higher (16.2%). The most frequently reported adverse experiences were of gastroi­ntestinal origin (6.1%), nausea (2.0%) and epigastralgia being most common amongst these.

No itraconazole-induced hepatitis was ob­served in the patient samples studied and according to the available post-marketing sta­tistics, no itraconazole-induced hepatitis has been reported in over 1.5 million prescriptions (Jan 1991).

During long-term treatment of onychomycosis, the observed percentage of increases on liver function tests (3.5%) was not higher than background incidence and compares favourably with the incidence (up to 12%) that occurred during ketoconazole ad­ministration. However, clinical experience is still insufficient to allow incidence calculations and for therapies longer than 30 days, liver function tests should be carried out monthly until more feedback has been obtained from longer thera­pies. A few cases of hypokalemia have been observed during long-term therapy at high dose (400 mg//day). [44]


  High risk patient groups Top


Experience with itraconazole in neonates and children is limited. On the basis of expe­rience in the treatment of tinea capitis and aspergillosis, the daily dosage of itraconazole can be calculated at 5 mg/kg, provided the child weighs less than 30 kg.

It is advised that itraconazole should not be used in these patients unless the potential benefit outweighs the potential risks.

Itraconazole was shown to increase the in­cidence of foetal abnormalities and produced adverse effects on the embryo at high doses in pregnant rats (40 mg/kg/day and higher) and mice (80 mg/kg/day). No studies are available on the use of itraconazole in pregnant women.

Therefore, itraconazole should be given, only in life-threatening cases of systemic of mycosis and when, in these cases, the poten­tial benefit outweighs the risk. It is recom­mended not to breast feed whilst taking itraconazole.

Single and repeated dose pharmacokinet­ics of itraconazole in elderly subjects are similar to those in young and middle-aged adults. Therefore, no dose-adjustments are required in elderly patients.

In a pharmacokinetic trial in patients with renal insufficiency, the oral bioavailability of itraconazole was lower than that in normal vol­unteers. Monitoring of the itraconazole plasma concentrations and dose adaptation are there­fore advisable. It was further found in this trial that plasma protein binding of itraconazole is not changed by renal insufficiency.

In cirrhotic patients, peak plasma concen­trations were 50% lower than in healthy sub­jects and may indicate a decreased drug ab­sorption. In contrast, terminal half-lives were somewhat prolonged. The conclusion of this pharmacokinetic study is that the oral bioavailability of itraconazole is not altered in patients with liver cirrhosis [4]


  Drug interactions Top


Effects of itraconazole on other drugs.

Inductive or inhibitory effects of itraconazole on the hepatic cytochrome-P450 system have been investigated in several trials. Itraconazole in daily doses of 100 mg and 200 mg did not alter the clearance of antipyrine. Furthermore, 200 mg itraconazole for two weeks had no inducing effect on the disposition of the oral contraceptive combination of ethinyl oestradiol and norethisterone.

Administration of itraconazole 100 mg b.i.d. in AIDS patients did not affect the peak con­centration and area under the curve of AZT (zidovudine).

Itraconazole may interact with cyclosporin (observations at 400 mg/d), resulting in an in­crease in the cyclosporin concentration, with, in some cases, cyclosporin-associated renal toxicity necessitating an adjustment of the cyclosporin dose. It is therefore advised that cyclosporin blood concentrations and renal function should be monitored. The interaction was found to be reversible but its exact mechanism is unknown.

In vitro equilibrium dialysis experiments have shown that itraconazole does not change the plasma protein binding of other clinically important drugs such as imipramine, propranolol, diphenylhydantoin, diazepam, cimetidine, indomethacin, tolbutamide, sulphamethazine and warfarin. [4],[6]


  Effects of other drugs on itraconazole Top


Single-dose pharmacokinetics of itraconazole are not significantly altered by concurrent use of the H Z antagonists cimetidine and ranitidine.

Enzyme-inducing drugs such as rifampicin and phenytoin significantly reduce the bioavailability of oral itraconazole. On acute co­administration of 600 mg of rifampicin, itraconazole plasma concentrations were 80% higher than in the control state, indicating inhi­bition of itraconazole metabolism. Itraconazole plasma concentrations after a new itraconazole dose three days later were only 18% of those in the control state, which can be explained by strongly increased itraconazole clearance.

Phenytoin 100 mg t.i.d. for one week re­duced itraconazole plasma concentrations to 20% of those in the control state. The small change in the plasma protein binding of itraconazole at high therapeutic concentrations diphenylhydantoin is probably not clinically important. Monitoring of the itraconazole con­centrations is advised when enzyme-inducing agents are co-administered 48


  Acknowledgement Top


The authors are indebted to Lubin Jeffrey and van Grootel Carla for their help in prepar­ing and revising the manuscript.

 
  References Top

1.Van Custem J The in vitro antifungal spectrum of itraconazole. Mycoses, 1989; 32 : 7-13 (Suppl 1).  Back to cited text no. 1    
2.Van Custem J Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals. Mycoses, 1989; 32 14-34 (Suppl 1).  Back to cited text no. 2    
3.Vandenbosshe H Biochemical targets for antifungal azole derivatives: hypothesis on the mode of action. Curr. Top. Med. Mycol, 1985; 1 : 313-51.  Back to cited text no. 3    
4.Smith KJ, Warnock DW, Kennedy CTC et al. Azole resistance in Candida albicans. J. Med. Vet. Mycol., 1986; 24: 133-144.  Back to cited text no. 4    
5.Heykants J, Van Peer A, Van de Velde V, et al. The clinical pharmacokinetics of itraconazole : an over­view. Mycoses, 1989; 32 : 67-87 (Suppl 1).  Back to cited text no. 5    
6.Woestenborghs R, Lorreyne W, Heykants J Determi­nation of itraconazole in plasma and animal tissues by high-performance liquid chromatography. J. Chromatogr., 1987; 413 : 332-337.  Back to cited text no. 6    
7.Vandepitte J Expert report on the clinical documen­tation relating to the use of itraconazole in systemic mycoses. Clinical expert report on R51211 no. 119, June 1990.  Back to cited text no. 7    
8.De Beule K. Safety profile of itraconazole therapy in vaginal candidosis, dermatomycosis and onychomycosis. A review. Current Therapeutic Re­search.  Back to cited text no. 8    
9.Wesel S Itraconazole: a single-day oral treatment for acute vulvovaginal candidosis. Brit J. Clin. Pract., 1990; 44 (9) : 77-80 (Suppl 71).  Back to cited text no. 9    
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42.Willemsen M, De Doncker P, Cauwenbergh G etal. Post-therapeutic itraconazole levels remain up to 6 months in the nail : New implications for the treat­ment of onychomycosis. In : Clinical Dermatology in the year 2000. London, 22-25 May 1990, p.137.  Back to cited text no. 42    
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