Oral and Intravenous Itraconazole for Systemic Fungal Infections in Neutropenic Haematological Patients: Meeting Report

Prentice, H. G.; Caillot, Denis; Dupont, B.; Menichetti, F.; Schuler, U

doi:10.1159/000040923

Cited by 31 publications

(24 citation statements)

References 19 publications

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“…In clinical studies, it assumed that a trough value of at least 500 g/liter itraconazole is required to successfully prevent or treat invasive fungal disease (17,19), which both formulations achieve with doses of 200 mg or higher. Moreover, the variance in trough levels of the NCF of itraconazole was relatively low, which is in contrast to what is observed after oral treatment.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

Mouton

Peer²,

Beule³

et al. 2006

Antimicrob Agents Chemother

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Originally, itraconazole for parenteral administration was licensed in a 40% hydroxypropyl-beta-cyclodextrin (HPBCD) solution for intravenous administration. A novel formulation, the NanoCrystal formulation (NCF), was prepared. NCF consists of drug particles of approximately 200 to 300 nm. The pharmacokinetics of itraconazole and its hydroxy metabolite in healthy subjects were evaluated after single and multiple doses of itraconazole as NCF. In the single-ascending-dose (SAD) study, itraconazole doses were planned to range from 50 to 500 mg, while in the multiple-ascending-dose (MAD) study, itraconazole doses of 100, 200, and 300 mg as NCF were studied, as was one dose level (200 mg) as an HBPCD solution. Samples were collected in heparinized tubes at various time points and were analyzed by high-performance liquid chromatography to allow full pharmacokinetic analysis both after the first dose and on day 7. The results of both the SAD and the MAD studies indicated that there was a dose dependency in the half-life of itraconazole from the novel formulation, increasing from 44 h (100 mg) to more than 150 h (300 mg) once steady state was achieved. Similar dose-dependent effects were observed for the hydroxy metabolite. The areas under the concentrationtime curves for itraconazole and hydroxyitraconazole were also dose dependent. The pharmacokinetic profiles after 200-mg doses of itraconazole as NCF and HPBCD formulations were comparable with respect to the terminal half-life, both after a single dose and at steady state. NCF may provide an alternative to the HPBCD solution for the further optimization of antifungal treatment with itraconazole.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

Mouton

Peer²,

Beule³

et al. 2006

Antimicrob Agents Chemother

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“…The oral absorption of itraconazole when given in capsule form is erratic, especially in patients with hematologic malignancies, and itraconazole oral solution may require up to 10-15 days to produce therapeutic blood levels [11,12]. Thus, with itraconazole, it is advisable to start with the intravenous formulation for 2 days to reach therapeutic blood levels and then shift to the oral formulation [12].…”

Section: What Dose and Schedule Of Prophylactic Regimen Should Be Evamentioning

confidence: 99%

“…Thus, with itraconazole, it is advisable to start with the intravenous formulation for 2 days to reach therapeutic blood levels and then shift to the oral formulation [12].…”

Section: What Dose and Schedule Of Prophylactic Regimen Should Be Evamentioning

confidence: 99%

How to Improve the Design of Trials of Antifungal Prophylaxis among Neutropenic Adults with Acute Leukemia

Menichetti

2004

Clinical Infectious Diseases

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The risk for invasive fungal infections in patients with acute leukemia is generally low (4%-8%), and the routine use of fungal prophylaxis is not warranted except in specific high-risk groups that should be identified among this population. In a prophylactic study with a new agent, fluconazole or itraconazole oral solution represent good choices for the comparator because they are proven better than placebo or oral nonabsorbable antifungal agents in reducing the risk of invasive fungal infections in patients with acute leukemia. Because prophylaxis is most valuable when the risk of infection is high, patients with well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species) should be selected. The end points for antifungal prophylactic trials should focus on proven and probable invasive fungal infections. Superficial and mucosal fungal infections do not represent a primary end point for these studies. Poor compliance should be considered as an interruption of treatment due to side effects and should be included in the criteria for failure. Fungus-related mortality should be evaluated as a failure of prophylaxis, whereas overall mortality may be influenced by many other cofactors. Differences in gastrointestinal toxicity of antifungal agents may limit the use of double-blind designs in some situations.The risk of invasive fungal infections in patients with acute leukemia ranges from 4% to 8% [1][2][3] and is lower than the rate of 16%-18% observed in patients who have undergone hematopoietic stem cell transplantation [4,5]. Thus, the relevance of fungal prophylaxis in patients with acute leukemia has been less apparent, and the routine use of prophylaxis has not been thought to be warranted. However, antifungal prophylaxis might be warranted for patients with acute leukemia who have well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species), and we need carefully conducted studies involving such higher-risk patients, who may

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“…Oral and intravenous itraconazole is used in the therapy and primary and secondary prophylaxis of IA [111]. The oral formulation has a response rate of between 39-66%.…”

Section: Azolesmentioning

confidence: 99%

Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients

et al. 2001

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Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients. F. Reichenberger, J.M. Habicht, A. Gratwohl, M. Tamm. #ERS Journals Ltd 2002. ABSTRACT: Invasive pulmonary aspergillosis is a major cause of morbidity and mortality in neutropenic patients.Microbiological and serological tests are of limited value. The diagnosis should be considered in neutropenic patients with fever not responding to antibiotics, and typical findings on thoracic computed tomography scan. Whenever possible, diagnosis should be confirmed by tissue examination. Newer techniques, such as polymerase chain reaction may change the current diagnostic approach.Therapeutic strategies consist of prophylaxis in risk groups and the early application of antifungal agents in suspected or probable disease. Amphotericin B as desoxycholate or lipid formulation is the current standard medication in invasive infection, although it has major side effects. Its role is challenged by the new azole derivates, such as itraconazole and voriconazole, and the new echinocandins. Additional therapies with cytokines, such as granulocyte macrophage colony stimulating factor and interferon-c, and with granulocyte transfusions are under evaluation. In selected cases lung resection is of proven diagnostic and therapeutic value.This paper analyses the current understanding of the pathogenesis and epidemiology of invasive aspergillosis and reviews the actual diagnostic and therapeutic strategies for invasive pulmonary aspergillosis in neutropenic patients.

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Oral and Intravenous Itraconazole for Systemic Fungal Infections in Neutropenic Haematological Patients: Meeting Report

Cited by 31 publications

References 19 publications

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

How to Improve the Design of Trials of Antifungal Prophylaxis among Neutropenic Adults with Acute Leukemia

Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients

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