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

Hematological Malignancy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02372357
• Other study ID #: 2841/20 Feb 2012
• Status: Completed
• Phase: Phase 4
• First received: February 6, 2015
• Last updated: March 2, 2015
• Start date: February 2012
• Est. completion date: October 2014

Study information

• Verified date: March 2015
• Source: Universitaire Ziekenhuizen Leuven
• Contact: n/a
• Is FDA regulated: No
• Health authority: Romania: Ethics CommitteeRomania: National Agency for Medicines and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: October 2014
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 13 Years

Eligibility

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

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hematological Malignancy

Intervention

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.

Locations

Country	Name	City	State
Belgium	Catholic University Leuven - Department of Pharmaceutical and Pharmacological Sciences	Leuven	Vlaams-Brabant
Romania	Institutul Clinic Fundeni	Bucharest	Sector 2

Sponsors (2)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen Leuven	Institutul Clinic Fundeni Bucharest

Countries where clinical trial is conducted

Belgium,  Romania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	pharmacokinetic parameters of posaconazole	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.	One day at steady state posaconazole treatment	No
Secondary	Safety of posaconazole, focussing on nausea, vomiting and liver function abnormalities (according to the Common Terminology Criteria for Adverse Events (CTCAE classification).	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.	patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks	No
Secondary	Efficacy: patients are monitored for breakthrough infections according the the European Organisation for Research and Treatment of Cancer- Mycoses Study Group (EORTC-MSG) criteria.	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	patients will be followed for the duration of hospital stay, an expected average of 3-4 weeks	No