Development of Voriconazole Pharmacokinetics and Metabolism in Children and Adolescents

Completed

• Conditions: Pharmacokinetics; Voriconazole
• Interventions: Drug: Midazolam/Ranitidine/Esomeprazole

• Registration Number: NCT01976078
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-09
• Study First Submitted: 2013-09-18
• Study First Submitted QC: 2013-10-29
• Study First Posted: 2013-11-05
• Primary Completion: 2015-04-22
• Study Completion: 2015-04-22
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-16
• Last Update Posted: 2018-02-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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)

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Midazolam/Ranitidine/Esomeprazole	Midazolam/Ranitidine/Esomeprazole	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.

Primary Outcome Measures

Name	Time	Method
Voriconazole steady-state pharmacokinetics	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

Name	Time	Method
Voriconazole drug metabolizing enzyme activity	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.

Trial Locations

Locations (1)

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States