Clinical trial NCT02372357: A New Dosing Regimen for Posaconazole Prophylaxis in Children Based on Body Surface Area
Official title: A New Dosing Regimen for Posaconazole Prophylaxis in Children Based in Body Surface Area
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hematological Malignancy
Keywords: chemotherapy
stem cell transplantation
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: Institutul Clinic Fundeni
First posted: 2015-02-26
Enrollment: 14
Sex: ALL
Minimum age (years): 2
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: A new prophylactic posaconazole dosing regimen of 120mg/m² tid is evaluated pharmacologically in children 13 years and younger, suffering from a hematologic malignancy.

Detailed description: Invasive fungal infections (IFI), especially candidiasis and aspergillosis, are a serious threat to immunocompromised pediatric patients. Because diagnosis of IFI in pediatric patients is difficult, due to the lack of specific clinical and radiological signs and the low sensitivity of blood cultures, antifungal prophylaxis would largely optimize management of IFI in this setting. However, antifungal prophylaxis remains a matter of debate, as no clear consensus has yet been reached about the optimal drug. Very limited pediatric data are available, and current guidelines are mainly based on extrapolation of adult data. Fluconazole remains the drug of choice in many centers, despite its non-mould active spectrum. Itraconazole, liposomal amphotericin B and nebulized lipid-formulations of amphotericin B are often used off-label, although neither their pharmacokinetics (PK), nor their efficacy and safety have been documented in a proper way. Voriconazole is registered for children older than 2 years of age, mainly in the treatment setting. Moreover, its extremely variable PK profile, uncertainty about adequate exposure and risk for hepatotoxicity and neurotoxicity do not favor the use of voriconazole in this setting. Finally, micafungin only has low recommendation in the prophylactic setting, due to the possible risk of liver tumours.

Posaconazole would be the ideal antifungal drug to be used prophylactically in children for many reasons. It has a broad spectrum of activity, including emerging moulds like Aspergillus spp. and Zygomycetes. It has shown to be superior over fluconazole and itraconazole in preventing IFI in adults and it has a favorable safety profile, with nausea and vomiting being the most frequently encountered adverse events. However, lack of pharmacokinetic (PK) data in children younger than 13 years of age, results in only a marginal recommendation in current guidelines \[8\]. Little information is available about the correct dosing regimen of the available oral suspension in young pediatric patients, and similar to what is observed in adults, often very low posaconazole plasma concentrations (PPCs) are being measured. Therefore, therapeutic drug monitoring (TDM) is recommended to reach adequate PPCs above 0.5mg/L or 0.7 mg/L followed by increasing the dose as needed.

In this study, the pharmacokinetics of a newly introduced dosing regimen for posaconazole oral suspension is investigated, based on body surface area (BSA), used prophylactically in immunocompromised children under the age of 13.

Pediatric patients, admitted to the hospital to receive chemotherapy or hematopoietic stem cell transplantation are treated prophylactically with posaconazole 120mg/m² tid.

At steady state (after at least 7 days of posaconazole treatment), 9 plasma samples are collected in these patients to calculate the area under the curve and other relevant PK parameters as maximum and minimal plasma concentrations, volume of distribution, halflife and clearance rate.

Finally, these results will be compared to adult data in literature to evaluate whether 120mg/m² tid an adequate dosing regimen in children.

Eligibility criteria: Inclusion Criteria:

* 2-13 years of age
* hematological malignancy
* need for antifungal prophylaxis because of neutropenia caused by chemotherapy and/or hematopoietic stem cell transplantation.

Exclusion Criteria:

* \<2 years of age
* \> 13 years of age

Primary outcomes:
measure: pharmacokinetic parameters of posaconazole
timeFrame: One day at steady state posaconazole treatment
Secondary outcomes:
measure: Safety of posaconazole, focussing on nausea, vomiting and liver function abnormalities (according to the Common Terminology Criteria for Adverse Events (CTCAE classification).
timeFrame: patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks
measure: Efficacy: patients are monitored for breakthrough infections according the the European Organisation for Research and Treatment of Cancer- Mycoses Study Group (EORTC-MSG) criteria.
timeFrame: patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Catholic University Leuven - Department of Pharmaceutical and Pharmacological Sciences
state: Vlaams-Brabant
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
state: Sector 2
Study officials:
affiliation: Institutul Clinic Fundeni, Bucarest, Romania
name: Anca Colita, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Catholic University Leuven, Leuven, Belgium
name: Kim Vanstraelen, PharmD
role: PRINCIPAL_INVESTIGATOR
References: