Support Care Cancer DOI 10.1007/s00520-006-0125-7
Arne Simon Mette Besuden Sandra Vezmar Carola Hasan Dagmar Lampe Sigrid Kreutzberg Axel Glasmacher Udo Bode Gudrun Fleischhack
Received: 5 February 2006 Accepted: 5 July 2006 # Springer-Verlag 2006
Arne Simon and Mette Besuden Both authors contributed equally to this manuscript. A. Simon (*) . M. Besuden . S. Vezmar . C. Hasan . U. Bode . G. Fleischhack Department of Pediatric Hematology/ Oncology, Children’s Hospital, Medical Center University of Bonn, Adenauerallee 119, 53113 Bonn, Germany e-mail:
[email protected] Tel.: +49-228-2873254 Fax: +49-228-2873301 D. Lampe . S. Kreutzberg Institute for Toxicology–Clinical Toxicology and Poison Information Centre, Berlin, Germany A. Glasmacher Department of Internal Medicine I, University of Bonn, Bonn, Germany
ORIGINA L ARTI CLE
Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants
Abstract Goal of work: During the renovation works at our institution, the incidence density for invasive aspergillosis (IA) increased from 10 days), autologous stem cell transplantation, acute myeloblastic leukemia or relapsed acute lymphoblastic leukemia, or high-dose steroids >3 weeks. Materials and methods: In this openlabel, prospective observational study, ITC was given in ITC solution or capsule. Trough concentrations were measured in plasma with high-performance liquid chromatography after at least 7 days of treatment. Doses were adjusted to target plasma trough ITC concentrations ≥0.5 mg/l. Results: From 2001 to 2005, 39 pediatric cancer patients received 44
Introduction The prevention of invasive Aspergillus spp. infections (invasive aspergillosis, IA) is a task of high priority in pediatric cancer patients [1] because IA negatively impacts quality of live, duration of hospitalization, and survival [2, 3]. Within the hospital, an interdisciplinary approach aims at the reduction of exposure to Aspergillus conidia.
prophylactic ITC cycles; 102 trough plasma concentrations were measured after oral administration. Plasma target concentrations >0.5 mg/l were achieved with both formulations. A median dose of 8 mg kg−1 day−1 (3.5– 16.0 mg kg−1 day−1) was necessary in pediatric oncology patients. The bioavailability of the liquid formulation was significantly lower when the solution was given by a feeding tube. Adverse effects (gastrointestinal, elevated transaminases, and one hemolysis) which led to the cessation of the ITC prophylaxis were reported in 11% of all courses. No breakthrough infection was seen in this pediatric population. Conclusion: Oral ITC offers a feasible and inexpensive option for antifungal prophylaxis in selected pediatric cancer patients. Drug monitoring and meticulous consideration of possible interactions and adverse effects are mandatory. Keywords Itraconazole . Pediatric cancer patients . Pharmacokinetics
Environmental reservoirs of Aspergillus spp. inside the health care setting should be actively searched and eliminated [4, 5]. The unit epidemiology of IA is at best described as incidence density in terms of probable plus proven cases of IA (referring to the consensus criteria of the European Organization for Research and Treatment of Cancer from 2002 [6]) per 1,000 inpatient days. In 1998, the incidence
density of IA in our unit had been below 0.5/1,000 inpatient days [7]. In April 2001, a new module ( http:// www.onkopaednki.de) for the surveillance of nosocomial infections was started. In the first 12 months of this surveillance, five newly diagnosed IA cases were detected (two proven with multifocal involvement including the CNS, and three with probable IA of the lung). The resulting incidence density of 0.99/1,000 inpatient days in 2001 was much higher than the 1998 study, indicating an increased overall risk in our unit. Severe IA cases were even observed in patients who were not suspected to face a relevant risk of this complication, i.e., patients with neuroblastoma. Most probably, the IA rate in our unit increased as a result of ongoing reconstruction and renovation work in and beneath the hospital [8]. Prospectively randomized studies in adults had shown significant activity of itraconazole (ITC) in patients with febrile neutropenia and invasive pulmonary aspergillosis [9, 10]. The data available in 2001 [11, 24] did not display substantial differences between the pharmacokinetics of ITC in adults and children older than 12 months [12]. The bioavailability of the HBC oral solution was reported to be 40–60% higher than the bioavailability of the capsules in particular in fasting state [13, 14]. Considering the application of the oral solution as a feasible option even in younger children or in children with feeding tubes, the attending pediatric oncologists at our institution decided to use ITC in terms of prophylaxis. Regarding the results of Glasmacher and co-
Table 1 Characteristics of patients receiving ITC prophylaxis Patient characteristics
n
Number of patients Itraconazole (ITC) prophylactic cycles Age in years: median (range) Male/female (%) Weight (kg)
39 44 6.4 (0.7–11,5) 20/19 (51/49) Median 26 (interquartile range 8–45) No (%)a 6 (15) 9 (23) 2 (5) 2 (5) 5 (13) 13 (33)
Diagnosis Acute lymphoblastic leukemia Acute myeloblastic leukemia Systemic LHX Lymphoma Neuroblastoma Other solid tumors with high-dose chemotherapy CNS tumors with prolonged steroids 2 (5) Patients with relapsed malignancyb 20 (45) a
Proportions refer to 39 patients (100%) Proportions refer to 44 itraconazole cycles (100%)
b
workers, a drug monitoring approach to optimize the efficacy of ITC prophylaxis was implemented [13, 15]. This strategy is aimed at plasma trough concentrations (ITC) above 0.5 mg/l [16, 17].
Ethical considerations Although ITC has been widely used in children with superficial skin mycoses [18] and in pediatric intensive care patients with invasive candidemia [19, 20], only few clinical trials investigated the pharmacokinetics of this substance in children with cancer [21]. No approval for the use of ITC in children has been applied for by the manufacturer. On the other hand, in 2001, no alternative oral formulation of an antifungal agent with proven in vitro activity against IA was available [22]. After personal information about the specific indication and the possible adverse events, written informed consent to the use of ITC and to the obligatory monitoring of the ITC plasma concentrations was achieved from the patients, their parents, or their legal guardians.
Materials and methods Study objectives The primary objective of this study was to investigate trough concentrations of ITC and its active metabolite hydroxy-ITC in pediatric cancer patients outside the allogenic stem cell transplantation setting after the oral administration of the solution or the capsule. Thorough clinical observation and laboratory monitoring assured the critical assessment of feasibility of this approach and the timely detection of adverse reactions related to the use of ITC. As we could not refer to a prospectively randomized control group, our study concentrated on those adverse events, which were addressed to the use of ITC by the attending physicians and resulted in a cessation of the ITC treatment. Inclusion criteria and treatment schedule This prospective, uncontrolled, open-label study group included patients with hematological malignancies and solid tumors. All patients received conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. The decision to use ITC for prophylaxis in an individual patient was made at the discretion of the attending physicians based on a consensus discussion between the pediatric oncologists and infectious disease specialists. The most significant criteria supporting the decision for an antifungal prophylaxis were (a) a suspected duration of neutropenia of more than 10 days, (b) eligibility
Statistical analysis
for a high-dose chemotherapy regimen with autologous peripheral venous stem cell transplantation, and (c) specific underlying diseases (i.e., AML) and (d) disease status (first illness or relapse). In patients receiving vincristine or vinblastine as a component of the chemotherapy regimen, ITC was completely avoided or stopped at least 5 days before the administration of VCR to avert an ITC-induced increase in VCR neurotoxicity [23]. The recommended dose for the ITC oral solution in children was 5 mg kg−1 day−1 [11, 24]. Corresponding recommendations for the capsule were not available [12]. Hitherto, no data were published on plasma trough concentrations in pediatric patients after the administration of ITC capsules. Patients received the oral solution (Sempera® liquid; 10 mg/ml; Janssen-Cilag GmbH, Neuss, Germany) refrigerated to overcome the unpleasant taste or—in case of intolerance and a body weight >20 kg—the capsule (Sempera®; 50 and 100 mg; Janssen-Cilag GmbH, Neuss, Germany) with a starting dose of 5 mg kg−1 day−1 divided in two single doses. The dose was adjusted according to plasma trough concentrations on days 7–9 of treatment measured in the morning at about 12 h after the last ITC application. A loading dose (to achieve the target trough concentrations earlier) was not routinely administered although this may reasonably be considered in adolescents and adults. We wanted to avoid gastrointestinal side effects at the beginning of the treatment, which might have led to the early rejection of the medication by the patients and their caregivers.
Between February 2001 and April 2005, 44 courses of oral ITC were given to 39 patients (19% of all 210 pediatric oncology patients admitted to the unit during the study period), who fulfilled the inclusion criteria and received at least one course of ITC prophylaxis. Table 1 shows the patients’ characteristics; Fig. 1 refers to the distribution of the underlying conditions and the proportion of patients with relapsed malignancy. Nearly half of all cycles (45%) were administered to patients with relapsed malignancy. Prophylactic ITC was given for a median of 27 days (range 6–246 days; interquartile range 14–79 days; 2,560 cumulative treatment days). The following percentages (%) always refer to all 44 treatment courses (100%). A loading dose was administered in only seven treatment cycles (16%). Three patients were not able to swallow the oral preparation and not in the condition to get a feeding tube. They received ITC intravenously (5 mg kg−1 day−1 in two divided doses) (Sporanox®; Janssen-Cilag AG, Wycombe, UK).
Detection of plasma concentrations
Plasma trough concentrations
After 7–10 days of ITC treatment, the first blood sample was taken in the morning 12 h after the last ITC administration and tested for ITC and its main metabolite hydroxy-ITC by HPLC as described previously [13, 25] (isocratic, reverse phase, Diode Array Detection; 200 μl EDTA plasma, internal standard R 51012, acetonitril deproteinization). For calibration, blank sera were spiked with ITC and hydroxy-ITC in the range from 0.05 to 4.0 mg/l. The limit of detection was 0.03 mg/l, while the limit of quantification was 0.1 mg/l. ITC, hydroxy-ITC, and the internal standard R 51012 were obtained from JanssenCilag. Analysis was performed on the day the sample arrived at the laboratory. The results were sent by fax to the hospital. ITC and hydroxy-ITC showed excellent stability in EDTA-blood samples stored at room temperature up to 6 days with a standard deviation for ITC of 0.031 μg/ml, coefficient of variation of 2.9%, OH-ITC standard deviation of 0.086 μg/ml, and coefficient of variation of 4.0% (please contact
[email protected] for further information).
The results of repeated measurements of 102 plasma trough concentrations in 44 orally administered prophylactic treatment courses are illustrated in Fig. 2. There was a significant correlation between dose and trough concentrations (p=0.018). Simultaneous measurement of plasma concentrations of ITC and its metabolite hydroxy-ITC showed a strong correlation (p=0.001); the concentration of the active metabolite was almost two times higher than the concentration of the parent compound (data not shown). No significant difference in median trough concentrations was detected depending on the oral formulation (solution vs capsule) (p=0.065). Only patients who received the oral solution without a feeding tube had significantly higher trough concentrations vs patients who received the ITC capsule (p=0.02.). Patients in whom ITC was administered through a feeding tube (to overcome compliance problems or difficulties in swallowing) had significantly lower trough concentrations than patients who were able to swallow the oral medication (p=0.049). In the dosing range of 7–10 mg kg−1 day−1, protective trough concentrations were reached in most patients no matter what oral formulation had been used (solution with no tube vs
SPSS 12.0 (SPSS, Chicago, IL, USA) was used with the χ2 test or Fisher’s exact test for discontinuous variables and the Mann–Whitney U test for continuous variables. Tests of significance were two-sided, and p
