REVIEW. Haematology, The Royal Free Hospital, London, UK

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1 REVIEW Current experience with itraconazole in neutropenic patients: a concise overview of pharmacological properties and use in prophylactic and empirical antifungal therapy A. Glasmacher 1 and A. Prentice 2 1 Department of Internal Medicine I, University of Bonn, Bonn, Germany and 2 Department of Haematology, The Royal Free Hospital, London, UK ABSTRACT Itraconazole is a triazole broad-spectrum antifungal agent that can be given as capsules, oral solution or intravenous solution. Bioavailability in neutropenic patients is different between capsules (c. 23%) and oral solution (c. 55%). A dose response relationship has been established for the use of itraconazole in antifungal prophylaxis: HPLC-determined trough concentrations of itraconazole need to be above 500 ng ml for effective prevention of invasive Aspergillus infections. A meta-analysis of 13 randomised clinical trials and 3597 neutropenic patients with haematological malignancies has demonstrated a 53% reduction in the incidence of invasive Aspergillus infections with a sufficient dose of itraconazole. Two randomised clinical trials evaluated itraconazole for empirical antimycotic therapy in neutropenic patients with persisting fever despite broad-spectrum antibiotic therapy in comparison to conventional amphotericin B. Both demonstrated significantly reduced nephrotoxicity and at least comparable efficacy. In conclusion, itraconazole should be regarded as the standard for antifungal prophylaxis in high-risk patients and a valuable therapeutic option for empirical antifungal therapy in these patients. Keywords Antifungal prophylaxis, empirical antimycotic, invasive fungal infections, itraconazole Clin Microbiol Infect 2006; 12 (suppl 7): INTRODUCTION Itraconazole is a broad-spectrum triazole antifungal agent that was first introduced for use in patients with invasive fungal infections in 1987, when amphotericin B and fluconazole (new at that time) were the limited options for effective systemic therapy [1,2]. The form in which itraconazole was first used clinically was a capsule containing sugar-coated pellets. This was extremely successful in the treatment of fungal infections of skin and nails [3] but, despite some initially encouraging results, did not deliver sufficiently reliable bioavailability in neutropenic patients. The achlorhydria, mucositis, nausea and anorexia that complicate the management of these patients reduce significantly the intake and absorption of the drug Corresponding author and reprint requests: A. Glasmacher, Department of Internal Medicine I, University of Bonn, Bonn, Germany glasmacher@uni-bonn.de [4 6]. It is estimated that only about 22% of the substance is taken up by the patient in this clinical situation [7]. The formulation of the drug changed with the production of an oral solution of this highly lipophilic drug. Establishing a new principle in drug galenics, b-hydroxy-propyl-cyclodextrin, an oligosaccharide formed from seven glucose molecules, was used to incorporate itraconazole into an aqueous solution that could be swallowed and absorbed or infused intravenously [8 10]. Externally hydrophilic and internally lipophilic, cyclodextrin brings itraconazole into the systemic circulation, where it separates instantaneously. Cyclodextrin is inert and undergoes renal elimination without any metabolism. With these new oral and intravenous solutions, new trials were designed to evaluate the efficacy of itraconazole in antimycotic prophylaxis, in empirical antifungal therapy and, to a lesser extent, in the treatment of proven invasive fungal infections. At the same time, clearer data on the drug s dose response relationship became Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Glasmacher and Prentice Current experience with itraconazole in neutropenic patients 85 Table 1. The role of itraconazole in antifungal treatment strategies Clinical problem Role of itraconazole References Prevention of invasive fungal infections Empirical antifungal therapy Bioavailability Drug drug interaction Only antifungal agent with clear evidence that it prevents invasive fungal infections, including those caused by Aspergillus, in neutropenic patients with haematological malignancies Efficacy comparable to that of conventional amphotericin B; much lower toxicity Available as oral or intravenous solution (loading dose and drug monitoring required) Co-administration with drugs that are metabolised by cytochrome P450 3A4 to be avoided or adjusted for [31,32] [52,53] [7,11,34,54] (Hurlé, this issue) available and explained some of the earlier disappointments. This article reviews the most important pharmacological and clinical data on itraconazole and attempts to define its role in today s much larger armamentarium of antifungal agents (Table 1). CLINICAL PHARMACOLOGY AND PHARMACODYNAMICS The bioavailability of itraconazole capsules in neutropenic patients has been estimated at 22%, while the oral solution achieves about 55% bioavailability [7,11,12]. Several papers have reviewed itraconazole s pharmacokinetic properties in detail [3,7,10,13 17]. The elimination halflife after a single dose is about 24 h, which increases to an apparent elimination half-life of 34 h in the steady state. Itraconazole is highly lipophilic and therefore it has a large volume of distribution (11 L kg). This means that without a loading dose it may take up to 14 days to achieve steady state [6,7]. Itraconazole s protein-binding fraction is high (99%), and therefore it cannot be removed by haemodialysis [18 20]. The drug is metabolised in the liver by the cytochrome P450 pathway, and it is a substrate and a strong inhibitor of the isoenzyme 3A4, which is an important regulator of drug elimination pathways. Safe use of itraconazole requires careful attention to its interactions with other drugs. In cases of renal insufficiency, dose reduction of oral itraconazole is not necessary, whereas the intravenous solution is contraindicated in patients with a creatinine clearance below 30 ml min. In patients with minor or moderate degrees of hepatic insufficiency, dosing of itraconazole does not need to be changed; the standard dose can be used initially and then adapted according to the drug monitoring results (recommended range ng ml itraconazole; see below) [17]. Itraconazole is the only azole that forms an active metabolite, hydroxy-itraconazole, which has the same spectrum of antimicrobial activity as the parent compound [5]. In the steady state, this metabolite is found at concentrations approximately two-fold those of the parent compound, indicating that total serum antifungal activity is much higher than that corresponding to the itraconazole concentration alone. Itraconazole inhibits 14-a-demethylase, the rate-limiting enzyme for the synthesis of ergosterol, which is an important component of the fungal cell membrane [6]. While its effects on Candida spp. are fungistatic, it can achieve fungicidal activity on Aspergillus spp. at higher doses [21,22]. DEFINITION OF THE TARGET DRUG CONCENTRATION An early study of the efficacy of antifungal prophylaxis with itraconazole in neutropenic patients found a lower rate of invasive fungal infections in patients who had serum concentrations above 250 ng ml for at least 2 weeks [23]. In

3 86 Clinical Microbiology and Infection, Volume 12 Supplement 7, 2006 the absence of any further research into the effective level, a trough concentration of 250 ng ml itraconazole (measured by HPLC) has been considered to be optimal [16]. The additional concentration of hydroxy-itraconazole gives a total serum concentration of c. 750 ng ml (250 ng ml itraconazole plus 500 ng ml hydroxyitraconazole), which is probably not sufficient for most Aspergillus spp., for which MICs of c ng ml have been determined [24,25]. An in-vivo model of an experimental Aspergillus infection in immunosuppressed rabbits suggested that higher concentrations are necessary to achieve optimal reduction of the number of pulmonary colony-forming Aspergillus conidia [26]. When establishing the NCCLS recommendations on breakpoints for antifungal susceptibility testing, Rex et al. analysed itraconazole trough concentrations and response in patients with AIDS and oesophageal candidiasis [27]. In infections due to Candida spp. for which higher MICs were determined, clinical response rates were higher in patients when trough concentrations greater than 500 ng ml were achieved. Following on from these studies, we have analysed data from a cohort of consecutive neutropenic patients with haematological malignancies who have received myelosuppressive therapy and antifungal prophylaxis with itraconazole at increasing doses. Comparing itraconazole trough concentrations in patients with breakthrough invasive mycoses with those in patients who did not develop these infections, we demonstrated that the higher cut-off value (500 ng ml) was more likely to be protective against systemic fungal infection. In a subsequent case-control study, we compared itraconazole levels in 41 patients with invasive fungal infections (mostly proven or suspected invasive mould infections, with three invasive Candida infections) during antifungal prophylaxis with levels in 81 controls without an invasive fungal infection, matched for underlying disease and time of treatment. An itraconazole trough concentration above 500 ng ml was a statistically significant protective factor (OR 0.32, p 0.010), whereas a trough concentration above 250 ng ml was not (OR 0.39, p 0.084). Therefore, a trough concentration above 500 ng ml (ideally around 1000 ng ml) should be considered as a target concentration for itraconazole activity against invasive aspergillosis. ANTIFUNGAL PROPHYLAXIS IN NEUTROPENIC PATIENTS The inability of current diagnostic methods (clinical, culture- or non-culture-based, radiological) to provide a timely diagnosis [28] and the high mortality of invasive fungal infections in neutropenic patients [29,30] have led to an intensive search for alternative therapeutic strategies that do not depend on diagnostic measures. The most frequently used are empirical antifungal therapy, which is discussed below, and antifungal prophylaxis. We have recently reviewed the current data on antifungal prophylaxis with itraconazole [31,32], and focus here on a concise summary of the available evidence and current controversies regarding this concept. Fluconazole is still the most frequently used drug in antifungal prophylaxis, despite an astonishing lack of evidence to support this practice and its well-known intrinsic absence of activity against Aspergillus spp. Kanda et al. have produced a very clear meta-analysis of 16 studies with 3734 patients who received fluconazole in randomised trials of antifungal prophylaxis [33]. They clearly demonstrated that fluconazole is only active at higher doses and in patients receiving allogeneic stem-cell transplantation; patients with acute leukaemia did not profit from prophylaxis with this drug. The role of itraconazole and fluconazole in the setting of allogeneic stem-cell transplantation is reviewed elsewhere in this supplement. Our meta-analysis of 13 trials and 3597 patients unequivocally shows that the use of itraconazole in neutropenic patients with haematological malignancies and at sufficiently high doses (i.e., at least 400 mg day oral solution or 200 mg day intravenous solution) results in a statistically significant, 53% reduction in the relative risk of proven invasive fungal infections [31]. This meta-analysis showed, for the first time, that a drug could reduce the risk of invasive Aspergillus infections significantly by 46% and the mortality from invasive fungal infections by 45%. Antifungal prophylaxis with itraconazole is well-tolerated, with the exception of a higher rate of nausea and vomiting due to the cyclodextrin content of the oral solution and a higher rate of hypokalaemia [32,34]. Severe hepatic and renal toxicity was seen in one trial, where relatively high doses of itraconazole were associated with

4 Glasmacher and Prentice Current experience with itraconazole in neutropenic patients 87 prolonged and presumably toxic levels of the cytotoxic drug cyclophosphamide, which was given concomitantly with the itraconazole, as conditioning therapy prior to stem-cell transplantation, and which is metabolised by cytochrome P450 isoenzymes [35,36]. This additional toxicity was no longer observed when the start of itraconazole treatment was delayed until stem-cell re-infusion, which allows significant clearance of cyclophosphamide metabolites. We are not aware of any reports of such an interaction with any other alkylators, anthracyclines or antimetabolites, but itraconazole cannot be given close to the time of administration of vinca alkaloids, because of an interaction leading to the risk of potentially fatal neurotoxicity. Many other drugs interact with itraconazole, and the prescribing physicians should be aware of these interactions and the various ways of minimising their effects. These interactions are summarised in a previous review by one of the authors [6] and elsewhere in this supplement. These interactions can be divided into those affecting the level of itraconazole and those affecting the level of the interacting drug. Metabolism of itraconazole is induced by rifampicin, carbamazepine, phenytoin, phenobarbitone and isoniazid. Itraconazole reduces the rate of metabolism of cyclosporin, tacrolimus and digoxin. Adjustment of the doses of itraconazole or these interacting drugs may achieve safe and effective levels of either. Concomitant use of midazolam, triazolam, cisapride (no longer available under licence in some EU countries), terfenadine and astimazole should be avoided, however, because itraconazole can rapidly induce clinically dangerous levels of these drugs. Concomitant use with calcium channel blockers should also be avoided, or at least the QT interval should be monitored carefully if concomitant use is unavoidable. Coumarin derivatives can also be potentiated, so the International Normalized Ratio (INR) should be monitored carefully in patients needing warfarin and itaconazole simultaneously. As nausea and vomiting are common sideeffects of both leukaemia-related myelosuppressive chemotherapy and the conditioning therapy of full intensity used prior to stem-cell transplantation, oral intake of drugs cannot always be maintained. Therefore, the availability of an intravenous formulation of itraconazole allows more consistent bioavailability and compliance, as demonstrated by the study of Winston et al. [37,38]. The most important criticism of antifungal prophylaxis is that it is unselective. All patients receive the drug, whereas only c. 15% (the average incidence in neutropenic patients with haematological malignancies in the untreated control arms of our meta-analysis) would have eventually developed an invasive fungal infection. The balance of benefit vs. risk is weighted in favour of prophylaxis, however, by the combination of the devastating effects of an invasive infection and the relatively low toxicity of the azoles. Furthermore, an analysis of the number-to-treat, which greatly depends on the baseline risk, showed that among patients with a 15% risk of invasive fungal infections, 13 patients have to be treated to avoid one invasive fungal infection [31]. This suggests an additional cost effect balance in favour of prophylaxis with itraconazole against invasive fungal infections [32,37,39]. Antifungal prophylaxis has been criticised because there is no evidence that it can reduce overall mortality. Most studies, however, have not extended their follow-up period long enough to observe such an effect, which would probably be very difficult to separate from other factors such as the underlying disease and its therapy. Considering the immense rate of morbidity and the cost of invasive fungal infections, however, the prevention of these infections is a target that is worthwhile in its own right. In conclusion, we recommend the use of antifungal prophylaxis with itraconazole in all patients with haematological malignancies who have received myelosuppressive chemotherapy with an expected duration of neutropenia of more than 10 days, except for those who are given vinca alkaloids. EMPIRICAL ANTIFUNGAL THERAPY The results of two randomised trials in the 1980s led to the conventional use of intravenous antifungal therapy in neutropenic patients who had persistent fever despite broad-spectrum antibiotic therapy for 3 5 days. This practice probably accounts for the greatest part of spending on antifungal drugs [40]. After the initial proof of concept [41,42], a series of studies tested different antifungal agents, with defervescence as the main outcome. This

5 88 Clinical Microbiology and Infection, Volume 12 Supplement 7, 2006 endpoint was, however, rejected by the regulating authorities, and colleagues in the USA then proposed a combined outcome score [43 45] that consists of five elements and that has been used since. No comparative study so far has been sufficiently powered, however, to demonstrate differences in either the rate of breakthrough invasive fungal infections following the start of systemic antifungal therapy or the overall response to that therapy. Itraconazole has been tested in two clinical trials that have used conventional amphotericin B as a comparator [46,47]. The basic characteristics of these trials have many comparable features. Important differences were that a treatment crossover was allowed and that patients who underwent allogeneic stem-cell transplantation, as well as patients with pneumonia, were included in the German trial [47]. Both trials demonstrated a comparable rate of breakthrough invasive fungal infections with amphotericin B, but a considerably lower rate of treatment discontinuation and nephrotoxicity. Therefore, itraconazole is a valuable alternative to conventional amphotericin B in empirical antifungal therapy in neutropenic patients with persistent fever [48,49]. PHARMACO-ECONOMIC ASPECTS A calculation by Tolley et al., presented at a meeting in 2003, demonstrated that the total cost of an antifungal strategy as used in the Winston study was 4789 (7057 euros) with itraconazole and 9792 ( euros) with fluconazole. The difference is explained mainly by the better efficacy of itraconazole. Also, van Gool et al. performed a similar economic analysis of empirical antifungal therapy based on the results of the trials of Boogaerts et al. and Walsh et al., and found that the total cost of treatment, including hospital stay, was lowest with the use of itraconazole [44,46,50]. CONCLUSIONS An evidence-based recommendation for the use of itraconazole (in sufficient doses of the oral or intravenous solution) is made for its application in antifungal prophylaxis for high-risk patients where invasive fungal infections, including those caused by Aspergillus spp., can be reduced by c. 50%. Therefore, we regard itraconazole prophylaxis as the standard therapy in patients at high risk for invasive fungal infections. Several choices are available for empirical antifungal therapy. Besides itraconazole, liposomal amphotericin B and caspofungin have demonstrated non-inferiority when compared with their comparators (conventional amphotericin B and liposomal amphotericin B, respectively [44,45]), whereas voriconazole has not [51]. All were clearly much better tolerated than conventional amphotericin B. There is a reasonable expectation that some of these alternative drugs will make conventional amphotericin B, with its severe renal and infusion-related toxicity, an orphan drug. ACKNOWLEDGEMENTS The writing of this article was supported by an unrestricted grant from Janssen-Cilag Ltd. The work on itraconazole at the University of Bonn was supported in part by Leukämie- Initiative Bonn e.v. We gratefully acknowledge the important contribution of C. Hahn, Bonn, to this research. REFERENCES 1. Cauwenbergh G, de Doncker P, Stoops K, De Dier AM, Goyvaerts H, Schuermans V. Itraconazole in the treatment of human mycoses: review of three years of clinical experience. Rev Infect Dis 1987; 9 (suppl 1): S146 S Van Cutsem J, Van Gerven F, Janssen PA. Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses: animal models. Rev Infect Dis 1987; 9 (suppl 1): S15 S Grant SM, Clissod SP. Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989; 37: Persat F, Marzullo C, Guyotat D, Rochet MJ, Piens MA. Plasma itraconazole concentrations in neutropenic patients after repeated high-dose treatment. Eur J Cancer 1992; 28A: Heykants J, van Peer A, van de Velde V et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32 (suppl 1): Glasmacher A, Molitor E, Mezger J, Marklein G. Antifungal prophylaxis with itraconazole in neutropenic patients: pharmacological, microbiological and clinical aspects. Mycoses 1996; 39: Glasmacher A, Hahn C, Molitor E, Sauerbruch T, Schmidt-Wolf IGH. Itraconazole trough levels in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-cyclodextrin oral solution or coatedpellet capsules. Mycoses 1999; 42: Hostetler JS, Hanson LH, Stevens DA. Effect of cyclodextrin on the pharmacology of antifungal oral azoles. Antimicrob Agents Chemother 1992; 36:

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