Clinical trial NCT01976078: Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
Official title: Ontogeny of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pharmacokinetics
Voriconazole
Keywords: Voriconazole
Pharmacokinetics
Ontogeny
Modeling
Bayesian
Lead sponsor: Children's Hospital Los Angeles
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2013-11-05
Enrollment: 45
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Children with an invasive fungal infection

Brief 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.


Eligibility criteria: Inclusion Criteria:

1. Participants will be enrolled before their 18th birthday.
2. Participant/parent/legal guardian must be able and willing to provide signed informed consent.
3. Laboratory values obtained within 7 days prior to study entry (obtained for clinical purposes)

   1. Hemoglobin ≥ 7.0 g/dL (transfusion dependence acceptable)
   2. Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 5 X upper limit of age-appropriate normal (ULN)
   3. Serum creatinine ≤ 3 X ULN

Exclusion Criteria:

1. Pregnancy
2. Active substance abuse or other psychiatric illness that would prevent adherence to the study protocol. Investigators will not record this information in the screening log, and the information will be obtained from existing documents in the medical record only.
3. Known hypersensitivity or intolerance to study medications
4. Not expected to survive \>1 week.
5. Weight \< 4.5 kg (blood volume draw limitations)

Primary outcomes:
measure: Voriconazole steady-state pharmacokinetics
timeFrame: During the 12 hours after a dose
Secondary outcomes:
measure: Voriconazole drug metabolizing enzyme activity
timeFrame: Within 12 hours after a study medication dosing
Other outcomes:
measure: Accuracy of computer software for Bayesian dose optimization of voriconazole in individual patients
timeFrame: Within 4 weeks of study completion for each subject
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
Study officials:
affiliation: Children's Hospital Los Angeles
name: Michael N Neely, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hope WW, Vanguilder M, Donnelly JP, Blijlevens NM, Bruggemann RJ, Jelliffe RW, Neely MN. Software for dosage individualization of voriconazole for immunocompromised patients. Antimicrob Agents Chemother. 2013 Apr;57(4):1888-94. doi: 10.1128/AAC.02025-12. Epub 2013 Feb 4.
citation: Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010 Jan 1;50(1):27-36. doi: 10.1086/648679.
citation: Neely M, Margol A, Fu X, van Guilder M, Bayard D, Schumitzky A, Orbach R, Liu S, Louie S, Hope W. Achieving target voriconazole concentrations more accurately in children and adolescents. Antimicrob Agents Chemother. 2015;59(6):3090-7. doi: 10.1128/AAC.00032-15. Epub 2015 Mar 16.