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Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01976078
Recruitment Status : Completed
First Posted : November 5, 2013
Last Update Posted : February 20, 2018
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Michael Neely, Children's Hospital Los Angeles

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.

Condition or disease Intervention/treatment
Pharmacokinetics Voriconazole Drug: Midazolam/Ranitidine/Esomeprazole

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Study Type : Observational
Actual Enrollment : 45 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Ontogeny of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents
Actual Study Start Date : September 2012
Actual Primary Completion Date : April 22, 2015
Actual Study Completion Date : April 22, 2015

Group/Cohort Intervention/treatment
All enrolled subjects will have a study pharmacokinetic visit where they will be given the above cocktail of drugs along with their clinically indicated voriconazole dose, followed by blood sampling over the next 12 hours.
Drug: Midazolam/Ranitidine/Esomeprazole
Each of the three drugs will be given at 10% of their usual doses for age/weight.

Primary Outcome Measures :
  1. Voriconazole steady-state pharmacokinetics [ Time Frame: During the 12 hours after a dose ]
    8 (after intravenous dosing) or 9 (after oral dosing) samples are taken after a voriconazole dose over a 12 hour timeframe.

Secondary Outcome Measures :
  1. Voriconazole drug metabolizing enzyme activity [ Time Frame: Within 12 hours after a study medication dosing ]
    At the time of the voriconazole dose used for the primary outcome, an intravenous or oral cocktail of "probe drugs", depending on the route of the voriconazole dose, consisting of midazolam, ranitidine, and esomeprazole will be administered. Using the samples collected for the primary outcome, concentrations of all three probe drugs and their major metabolites will be measured and used to compute activity of the relevant drug metabolizing enzymes.

Other Outcome Measures:
  1. Accuracy of computer software for Bayesian dose optimization of voriconazole in individual patients [ Time Frame: Within 4 weeks of study completion for each subject ]
    Using existing voriconazole pharmacokinetic data, we have constructed a population model of the drug's behavior in children and adults. We are testing the use of this model in study subjects to compare the doses predicted by the software to achieve actual, measured voriconazole concentrations obtained for routine clinical care after the study PK visit, with the real doses that were administered and resulted in those measured voriconazole concentrations.

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Children with an invasive fungal infection

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)

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 identifier (NCT number): NCT01976078

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United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Sponsors and Collaborators
Children's Hospital Los Angeles
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Principal Investigator: Michael N Neely, MD Children's Hospital Los Angeles
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Michael Neely, Associate Professor of Pediatrics, Children's Hospital Los Angeles Identifier: NCT01976078    
Other Study ID Numbers: CCI-11-00334
R01HD070996 ( U.S. NIH Grant/Contract )
First Posted: November 5, 2013    Key Record Dates
Last Update Posted: February 20, 2018
Last Verified: February 2018
Keywords provided by Michael Neely, Children's Hospital Los Angeles:
Additional relevant MeSH terms:
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Ranitidine bismuth citrate
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Histamine H2 Antagonists
Histamine Antagonists
Histamine Agents