Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
Status:
Completed
Trial end date:
2015-04-22
Target enrollment:
Participant gender:
Summary
The death rate in children from the invasive fungal infection called aspergillosis is more
than 50%. Voriconazole is the first-line therapy for this infection. In a previous
publication the investigators have shown a highly significant relationship between
voriconazole plasma concentrations and survival. However, voriconazole dosing is currently
poorly established, and plasma drug exposure varies between children by 400% or more, even
after intravenous dosing. The objective of this study is to investigate the reasons for this
variability in voriconazole pharmacokinetics (PK).In two studies, the investigators will
enroll 80 children/adolescents receiving oral or intravenous voriconazole, divided by age
under 2 years (n=15), and 2-18 years (n=65). From each patient the investigators will collect
the following: 1) a blood sample for detection of several genetic changes known to affect
drug metabolizing enzyme (DME) activity; 2) up to 9 blood samples after a voriconazole dose
for measurement of voriconazole ("PK sampling"); 3) follow-up samples after each PK sampling
visit if necessary to adjust the dose so that voriconazole concentrations in the blood are
satisfactory (known as therapeutic drug monitoring or TDM). At the time of the voriconazole
dose prior to the PK sampling, we will also give single IV or oral (corresponding to the
route of voriconazole administration) low doses of esomeprazole (an antacid), midazolam (a
sedative), and ranitidine (an antacid) as a cocktail to test or probe DME activity. All of
these medications are used commonly in children already. The investigators will estimate DME
activity or phenotype using ratios of probe drug metabolite to parent drug concentrations,
while simultaneously quantifying the amount of DME genetic material (mRNA) and protein in
white blood cells. The investigators will test associations between DME activity, mRNA,
protein, voriconazole PK, age, sex, and degree of illness. The investigators will also use a
computer program to integrate all these data to develop a comprehensive model that will
predict blood concentrations of voriconazole in children of all ages, as well as assist
physicians and pharmacists to dose voriconazole more accurately.The total study duration for
each subject will be until after the TDM follow up visit, generally about one week.
Details
Lead Sponsor:
Children's Hospital Los Angeles
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)