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A New Dosing Regimen for Posaconazole Prophylaxis in Children Based on Body Surface Area

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ClinicalTrials.gov Identifier: NCT02372357
Recruitment Status : Completed
First Posted : February 26, 2015
Last Update Posted : March 3, 2015
Sponsor:
Collaborator:
Institutul Clinic Fundeni
Information provided by (Responsible Party):
Ap.r Kim Vanstraelen, Universitaire Ziekenhuizen Leuven

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.

Condition or disease Intervention/treatment Phase
Hematological Malignancy Drug: Posaconazole prophylaxis 120 mg/m² tid Procedure: Blood sampling Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A New Dosing Regimen for Posaconazole Prophylaxis in Children Based in Body Surface Area
Study Start Date : February 2012
Actual Primary Completion Date : August 2014
Actual Study Completion Date : October 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Posaconazole 120mg/m² tid

Pediatric patients admitted to receive chemotherapy or hematopoietic stem cell transplantation for the treatment of a hematological malignancy are receiving Posaconazole prophylaxis 120 mg/m² tid.

At steady state, blood sampling will be performed: 9 blood samples will be taken during 1 dosing interval to evaluate the pharmacokinetics of posaconazole.

Drug: Posaconazole prophylaxis 120 mg/m² tid
Patients are receiving posaconazole to prevent invasive fungal infections in a dose of 120 mg/m² tid

Procedure: Blood sampling
During steady state treatment with posaconazole (at least 7 days), 9 blood samples are taken via a central venous catheter to evaluate the pharmacokinetics of posaconazole.




Primary Outcome Measures :
  1. pharmacokinetic parameters of posaconazole [ Time Frame: One day at steady state posaconazole treatment ]
    9 blood samples are taken during one day at steady state posaconazole plasma concentrations. The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Cmax, Cmin, Tmax, Area Under the Curve during 1 dosing interval and over 24 hours, Clearance, Distribution volume, Halflife.


Secondary Outcome Measures :
  1. Safety of posaconazole, focussing on nausea, vomiting and liver function abnormalities (according to the Common Terminology Criteria for Adverse Events (CTCAE classification). [ Time Frame: patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks ]
    Patients receiving posaconazole prophylactically are closely monitored for adverse events possibly related to the drug. They are clinically monitored for nausea, vomiting and diarrhea. Liver function abnormalities are scored according to the CTCAE classification.

  2. Efficacy: patients are monitored for breakthrough infections according the the European Organisation for Research and Treatment of Cancer- Mycoses Study Group (EORTC-MSG) criteria. [ Time Frame: patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks ]
    Patients receiving posaconazole prophylactically are closely monitored for the presence of an invasive fungal infection. Patients are closely followed in case an invasive fungal infection is suspected: Fever is monitored, radiography is performed and galactomannan is measured frequently. Invasive fungal infections are categorized according to the revised EORTC-MSG criteria



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Ages Eligible for Study:   2 Years to 13 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02372357


Locations
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Belgium
Catholic University Leuven - Department of Pharmaceutical and Pharmacological Sciences
Leuven, Vlaams-Brabant, Belgium, 3000
Romania
Institutul Clinic Fundeni
Bucharest, Sector 2, Romania, 023808
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Institutul Clinic Fundeni
Investigators
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Principal Investigator: Anca Colita, MD Institutul Clinic Fundeni, Bucarest, Romania
Principal Investigator: Kim Vanstraelen, PharmD Catholic University Leuven, Leuven, Belgium

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Responsible Party: Ap.r Kim Vanstraelen, PharmD, Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT02372357     History of Changes
Other Study ID Numbers: 2841/20 Feb 2012
First Posted: February 26, 2015    Key Record Dates
Last Update Posted: March 3, 2015
Last Verified: March 2015
Keywords provided by Ap.r Kim Vanstraelen, Universitaire Ziekenhuizen Leuven:
chemotherapy
stem cell transplantation
Additional relevant MeSH terms:
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Neoplasms
Posaconazole
Antifungal Agents
Anti-Infective Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs